25 - 20 Substance Use and Addictive Disorders

01 - 20.1 Introduction and Overview
20.1 Introduction and Overview
Substance Use and Addictive Disorders
20.1 Introduction and Overview
The most commonly used drugs have been part of human existence for thousands of
years. For example, opium has been used for medicinal purposes for at least 3,500
years, references to cannabis (marijuana) as a medicinal can be found in ancient
Chinese herbals, wine is mentioned frequently in the Bible, and the natives of the
Western Hemisphere smoked tobacco and chewed coca leaves. As new drugs were
discovered and new routes of administration developed, new problems related to their
use emerged. Substance use disorders are complicated psychiatric conditions and like
other psychiatric disorders, both biological factors and environmental circumstances are
etiologically significant.
This chapter covers substance dependence and substance abuse with descriptions of
the clinical phenomena associated with the use of 11 designated classes of
pharmacological agents: alcohol; amphetamines or similarly acting agents; caffeine;
cannabis; cocaine; hallucinogens; inhalants; nicotine; opioids; phencyclidine (PCP) or
similar agents; and a group that includes sedatives, hypnotics, and anxiolytics. A
residual 12th category includes a variety of agents not in the 11 designated classes, such
as anabolic steroids and nitrous oxide.
TERMINOLOGY
Various terms have been used over the years to refer to drug abuse. For example, the
term dependence has been and is used in one of two ways when discussing substance use
disorders. In behavioral dependence, substance-seeking activities and related evidence of
pathological use patterns are emphasized, whereas physical dependence refers to the
physical (physiological) effects of multiple episodes of substance use. Psychological
dependence, also referred to as habituation, is characterized by a continuous or
intermittent craving (i.e., intense desire) for the substance to avoid a dysphoric state.
Behavioral, physical, and psychological dependence are the hallmark of substance use
disorders.
Somewhat related to dependence are the related words addiction and addict. The
word addict has acquired a pejorative connotation that ignores the concept of substance
abuse as a medical disorder. Addiction has also been trivialized in popular usage, as in
the terms TV addiction and money addiction; however, the term still has value. There are
common neurochemical and neuroanatomical substrates found among all addictions,
whether it is to substances or to gambling, sex, stealing, or eating. These various
addictions may have similar effects on the activities of specific reward areas of the
brain, such as the ventral tegmental area, the locus ceruleus, and the nucleus
accumbens.
Other Terms
Codependence.
The terms coaddiction and, more commonly, codependency or
codependence are used to designate the behavioral patterns of family members who
have been significantly affected by another family member’s substance use or addiction.
The terms have been used in various ways and no established criteria for codependence
exist.
Enabling.
Enabling was one of the first, and more agreed on, characteristics of
codependence or coaddiction. Sometimes, family members feel that they have little or
no control over the enabling acts. Either because of the social pressures for protecting
and supporting family members or because of pathological interdependencies, or both,
enabling behavior often resists modification. Other characteristics of codependence
include unwillingness to accept the notion of addiction as a disease. The family
members continue to behave as if the substance-using behavior were voluntary and
willful (if not actually spiteful), and the user cares more for alcohol and drugs than for
family members. This results in feelings of anger, rejection, and failure. In addition to
those feelings, family members may feel guilty and depressed because addicts, in an
effort to deny loss of control over drugs and to shift the focus of concern away from
their use, often try to place the responsibility for such use on other family members, who
often seem willing to accept some or all of it.
Denial.
Family members, as with the substance users themselves, often behave as if
the substance use that is causing obvious problems were not really a problem; that is,
they engage in denial. The reasons for the unwillingness to accept the obvious vary.
Sometimes denial is self-protecting, in that the family members believe that if a drug or
alcohol problem exists, then they are responsible.
As with the addicts themselves, codependent family members seem unwilling to accept the notion that outside
intervention is needed and, despite repeated failures, continue to believe that greater willpower and greater efforts at
control can restore tranquility. When additional efforts at control fail, they often attribute the failure to themselves rather
than to the addict or the disease process, and along with failure come feelings of anger, lowered self-esteem, and
depression. A summary of some key terms related to substance use disorders is given in Table 20.1-1.
Table 20.1-1
Terms Used in Substance-Related Disorders
EPIDEMIOLOGY
The National Institute of Drug Abuse (NIDA) and other agencies, such as the National
Survey of Drug Use and Health (NSDUH), conduct periodic surveys of the use of illicit
drugs in the United States. As of 2012, it is estimated that more than 22 million persons
older than the age of 12 years (about 10 percent of the total US population) were
classified as having a substance-related disorder. Of this group, almost 15 million were
dependent on, or abused, alcohol (Fig. 20.1-1).
FIGURE 20.1-1
Substance dependence or abuse in the past year among persons age 12 or over: 2002–
2012. (From Substance Abuse and Mental Health Services Administration, Results from
the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH
Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and
Mental Health Services Administration; 2013.)
Figure 20.1-2 shows data from the surveys on the percentage of respondents who
reported using various drugs. In 2012, 669,000 persons were dependent on, or abused,
heroin; 1.7 percent (4.3 million) abused marijuana; 0.4 percent (1 million) abused
cocaine; and 2 million were classified as dependent on, or abuse of, pain relievers.
FIGURE 20.1-2
Dependence on, or abuse of, specific illicit drugs within the past year among persons
age 12 or older: 2010. (From Substance Abuse and Mental Health Services
Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of
National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville,
MD: Substance Abuse and Mental Health Services Administration; 2013.)
With regard to age at first use, those who started to use drugs at an earlier age (14
years or younger) were more likely to become addicted than those who started at a later
age. This applied to all substances of abuse, but particularly to alcohol. Among adults
aged 21 or older who first tried alcohol at age 14 or younger, 15 percent were classified
as alcoholics compared with only 3 percent who first used alcohol at age 21 or older.
Rates of abuse also varied according to age (Table 20.1-2). In 2012, the rate for
dependence or abuse is highest among adults age 18 to 25 (19 percent) compared to
youths age 12 to 17 (6 percent) and adults age 26 or older (7 percent). After age 21, a
general decline occurred with age. By age 65, only about 1 percent of persons have used
an illicit substance within the past year, which lends credence to the clinical observation
that addicts tend to “burn out” as they age.
Table 20.1-2
Illicit Drug Use in Lifetime, Past Year, and Past Month, by Detailed Age
Category: Percentages, 2011 and 2012
Table 20.1-3 summarizes data about the demographic characteristics of those who use
illicit drugs. More men than women use drugs; the highest lifetime rate is among
American Indian or Alaska Natives; whites are more affected than blacks or African
Americans; those with some college education use more substances than those with less
education; and the unemployed have higher rates that those with either part-time or fulltime employment.
Table 20.1-3
Illicit Drug Use in Lifetime, Past Year, and Past Month among Persons Aged
18 or Older, by Demographic Characteristics: Percentages, 2011 and 2012
Rates of substance dependence or abuse varied by region in the United States. In
2010, rates were slightly higher in the West (9 percent) and Midwest (9 percent) than in
the Northeast (8 percent) and South (8 percent). Rates were similar in small
metropolitan counties and large metropolitan counties (both at 9 percent) and were
lowest in completely rural counties (7 percent). Rates are also higher among persons on
parole or on supervised release from jail (34 percent vs. 9 percent). The number of
persons driving while under the influence of drugs or alcohol is on a decline. The
percentage driving under the influence of alcohol decreased from 14 percent in 2002 to
11 percent in 2010, and those driving under the influence of drugs decreased from 5
percent to 4 percent during the same period. A comprehensive survey of drug use and
trends in the United States is available at www.samhsa.gov.
ETIOLOGY
The model of substance use disorders is the result of a process in which multiple
interacting factors influence drug-using behavior and the loss of judgment with respect
to decisions about using a given drug. Although the actions of a given drug are critical
in the process, it is not assumed that all people who become dependent on the same
drug experience its effects in the same way or are motivated by the same set of factors.
Furthermore, it is postulated that different factors may be more or less important at
different stages of the process. Thus, drug availability, social acceptability, and peer
pressures may be the major determinants of initial experimentation with a drug, but
other factors, such as personality and individual biology, probably are more important
in how the effects of a given drug are perceived and the degree to which repeated drug
use produces changes in the central nervous system (CNS). Still other factors, including
the particular actions of the drug, may be primary determinants of whether drug use
progresses to drug dependence, whereas still others may be important influences on the
likelihood that drug use (1) leads to adverse effects or (2) to successful recovery from
dependence.
It has been asserted that addiction is a “brain disease,” that the critical processes that
transform voluntary drug-using behavior to compulsive drug use are changes in the
structure and neurochemistry of the brain of the drug user. Sufficient evidence now
indicates that such changes in relevant parts of the brain do occur. The perplexing and
unanswered question is whether these changes are both necessary and sufficient to
account for the drug-using behavior. Many argue that they are not, that the capacity of
drug-dependent individuals to modify their drug-using behavior in response to positive
reinforcers or aversive contingencies indicates that the nature of addiction is more
complex and requires the interaction of multiple factors.
Figure 20.1-3 illustrates how various factors might interact in the development of drug
dependence. The central element is the drug-using behavior itself. The decision to use a
drug is influenced by immediate social and psychological situations as well as by the
person’s more remote history. Use of the drug initiates a sequence of consequences that
can be rewarding or aversive and which, through a process of learning, can result in a
greater or lesser likelihood that the drug-using behavior will be repeated. For some
drugs, use also initiates the biological processes associated with tolerance, physical
dependence, and (not shown in the figure) sensitization. In turn, tolerance can reduce
some of the adverse effects of the drug, permitting or requiring the use of larger doses,
which then can accelerate or intensify the development of physical dependence. Above a
certain threshold, the aversive qualities of a withdrawal syndrome provide a distinct
recurrent motive for further drug use. Sensitization of motivational systems can increase
the salience of drug-related stimuli.
FIGURE 20.1-3
World Health Organization schematic model of drug use and dependence. (From
Edwards G, Arif A, Hodgson R. Nomenclature and classification of drug-and alcoholrelated problems. A WHO memorandum. Bull WHO. 1981;59:225, with permission.)
Psychodynamic Factors
The range of psychodynamic theories about substance abuse reflects the various popular
theories during the last 100 years. According to classic theories, substance abuse is a
masturbatory equivalent (some heroin users describe the initial “rush” as similar to a
prolonged sexual orgasm), a defense against anxious impulses, or a manifestation of
oral regression (i.e., dependency). Recent psychodynamic formulations relate substance
use as a reflection of disturbed ego functions (i.e., the inability to deal with reality). As
a form of self-medication, alcohol may be used to control panic, opioids to diminish
anger, and amphetamines to alleviate depression. Some addicts have great difficulty
recognizing their inner emotional states, a condition called alexithymia (i.e., being
unable to find words to describe their feelings).
Learning and Conditioning.
Drug use, whether occasional or compulsive, can be
viewed as behavior maintained by its consequences. Drugs can reinforce antecedent
behaviors by terminating some noxious or aversive state such as pain, anxiety, or
depression. In some social situations, the drug use, apart from its pharmacological
effects, can be reinforcing if it results in special status or the approval of friends. Each
use of the drug evokes rapid positive reinforcement, either as a result of the rush (the
drug-induced euphoria), alleviation of disturbed affects, alleviation of withdrawal
symptoms, or any combination of these effects. In addition, some drugs may sensitize
neural systems to the reinforcing effects of the drug. Eventually, the paraphernalia
(needles, bottles, cigarette packs) and behaviors associated with substance use can
become secondary reinforcers, as well as cues signaling availability of the substance,
and in their presence, craving or a desire to experience the effects increases.
Drug users respond to the drug-related stimuli with increased activity in limbic
regions, including the amygdala and the anterior cingulate. Such drug-related activation
of limbic areas has been demonstrated with a variety of drugs, including cocaine,
opioids, and cigarettes (nicotine). Of interest, the same regions activated by cocainerelated stimuli in cocaine users are activated by sexual stimuli in both normal controls
and cocaine users.
In addition to the operant reinforcement of drug-using and drug-seeking behaviors,
other learning mechanisms probably play a role in dependence and relapse. Opioid and
alcohol withdrawal phenomena can be conditioned (in the Pavlovian or classic sense) to
environmental or interoceptive stimuli. For a long time after withdrawal (from opioids,
nicotine, or alcohol), the addict exposed to environmental stimuli previously linked with
substance use or withdrawal may experience conditioned withdrawal, conditioned
craving, or both. The increased feelings of craving are not necessarily accompanied by
symptoms of withdrawal. The most intense craving is elicited by conditions associated
with the availability or use of the substance, such as watching someone else use heroin
or light a cigarette or being offered some drug by a friend. Those learning and
conditioning phenomena can be superimposed on any preexisting psychopathology, but
preexisting difficulties are not required for the development of powerfully reinforced
substance-seeking behavior.
Genetic Factors
Strong evidence from studies of twins, adoptees, and siblings brought up separately
indicates that the cause of alcohol abuse has a genetic component. Many less conclusive
data show that other types of substance abuse or substance dependence have a genetic
pattern in their development. Researchers recently have used restriction fragment
length polymorphism (RFLP) in the study of substance abuse and substance dependence,
and associations to genes that affect dopamine production have been postulated.
Neurochemical Factors
Receptors and Receptor Systems.
With the exception of alcohol, researchers
have identified particular neurotransmitters or neurotransmitter receptors involved with
most substances of abuse. Some researchers base their studies on such hypotheses. The
opioids, for example, act on opioid receptors. A person with too little endogenous opioid
activity (e.g., low concentrations of endorphins) or with too much activity of an
endogenous opioid antagonist may be at risk for developing opioid dependence. Even in
a person with completely normal endogenous receptor function and neurotransmitter
concentration, the long-term use of a particular substance of abuse may eventually
modulate receptor systems in the brain so that the presence of the exogenous substance
is needed to maintain homeostasis. Such a receptor-level process may be the mechanism
for developing tolerance within the CNS. Demonstrating modulation of neurotransmitter
release and neurotransmitter receptor function has proved difficult, however, and recent
research focuses on the effects of substances on the second-messenger system and on
gene regulation.
Pathways and Neurotransmitters
The major neurotransmitters possibly involved in developing substance abuse and
substance dependence are the opioid, catecholamine (particularly dopamine), and γaminobutyric acid (GABA) systems. The dopaminergic neurons in the ventral tegmental
area are particularly important. These neurons project to the cortical and limbic
regions, especially the nucleus accumbens. This pathway is probably involved in the
sensation of reward and may be the major mediator of the effects of such substances as
amphetamine and cocaine. The locus ceruleus, the largest group of adrenergic neurons,
probably mediates the effects of the opiates and the opioids. These pathways have
collectively been called the brain-reward circuitry.
COMORBIDITY
Comorbidity is the occurrence of two or more psychiatric disorders in a single patient at
the same time. A high prevalence of additional psychiatric disorders is found among
persons seeking treatment for alcohol, cocaine, or opioid dependence; some studies have
shown that up to 50 percent of addicts have a comorbid psychiatric disorder. Although
opioid, cocaine, and alcohol abusers with current psychiatric problems are more likely
to seek treatment, those who do not seek treatment are not necessarily free of comorbid
psychiatric problems; such persons may have social supports that enable them to deny
the impact that drug use is having on their lives. Two large epidemiological studies have
shown that even among representative samples of the population, those who meet the
criteria for alcohol or drug abuse and dependence (excluding tobacco dependence) are
also far more likely to meet the criteria for other psychiatric disorders also.
In various studies, a range of 35 to 60 percent of patients with substance abuse or
substance dependence also meets the diagnostic criteria for antisocial personality
disorder. The range is even higher when investigators include persons who meet all the
antisocial personality disorder diagnostic criteria, except the requirement that the
symptoms started at an early age. That is, a high percentage of patients with substance
abuse or substance dependence diagnoses have a pattern of antisocial behavior, whether
it was present before the substance use started or developed during the course of the
substance use. Patients with substance abuse or substance dependence diagnoses who
have antisocial personality disorder are likely to use more illegal substances; to have
more psychopathology; to be less satisfied with their lives; and to be more impulsive,
isolated, and depressed than patients with antisocial personality disorders alone.
Depression and Suicide.
Depressive symptoms are common among persons
diagnosed with substance abuse or substance dependence. About one third to one half of
all those with opioid abuse or opioid dependence and about 40 percent of those with
alcohol abuse or alcohol dependence meet the criteria for major depressive disorder
sometime during their lives. Substance use is also a major precipitating factor for
suicide. Persons who abuse substances are about 20 times more likely to die by suicide
than the general population. About 15 percent of persons with alcohol abuse or alcohol
dependence have been reported to commit suicide. This frequency of suicide is second
only to the frequency in patients with major depressive disorder.
DIAGNOSTIC CLASSIFICATION
There are four major diagnostic categories in the Diagnostic and Statistical Manual of
Mental Disorders, fifth edition (DSM-5): (1) Substance Use Disorder; (2) Substance
Intoxication; (3) Substance Withdrawal; and (4) Substance-Induced Mental Disorder.
Substance Use Disorder
Substance use disorder is the diagnostic term applied to the specific substance abused
(e.g., alcohol use disorder, opioid use disorder) that results from the prolonged use of the
substance. The following points should be considered in making this diagnosis. These
criteria apply to all substances of abuse.
A maladaptive pattern of substance use leading to clinically significant impairment or
distress, as manifested by 2 (or more) of the following, occurring within a 12-month
period:
recurrent substance use resulting in a failure to fulfill major role obligations at
work, school, or home (e.g., repeated absences or poor work performance related to
substance use; substance-related absences, suspensions, or expulsions from school;
neglect of children or household)
recurrent substance use in situations in which it is physically hazardous (e.g., driving
an automobile or operating a machine when impaired by substance use)
continued substance use despite having persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of the substance (e.g.,
arguments with spouse about consequences of intoxication, physical fights)
tolerance, as defined by either of the following:
a. a need for markedly increased amounts of the substance to achieve intoxication or
desired effect
b. markedly diminished effect with continued use of the same amount of the
substance
withdrawal, as manifested by either of the following:
a. the characteristic withdrawal syndrome for the substance
b. the same (or a closely related) substance is taken to relieve or avoid withdrawal
symptoms
6. the substance is often taken in larger amounts or over a longer period than was
intended
7. there is a persistent desire or unsuccessful efforts to cut down or control substance
use
8. a great deal of time is spent in activities necessary to obtain the substance, use the
substance, or recover from its effects
9. important social, occupational, or recreational activities are given up or reduced
because of substance use
10. the substance use is continued despite knowledge of having a persistent or recurrent
physical or psychological problem that is likely to have been caused or exacerbated by
the substance
11. craving or a strong desire or urge to use a specific substance.
Substance Intoxication
Substance intoxication is the diagnosis used to describe a syndrome (e.g., alcohol
intoxication or simple drunkenness) characterized by specific signs and symptoms
resulting from recent ingestion or exposure to the substance. A general description of
substance intoxication includes the following points:
The development of a reversible substance-specific syndrome due to recent ingestion
of (or exposure to) a substance. Note: Different substances may produce similar or
identical syndromes.
Clinically significant maladaptive behavioral or psychological changes that are due to
the effect of the substance on the central nervous system (e.g., belligerence, mood
lability, cognitive impairment, impaired judgment, impaired social or occupational
functioning) and develop during or shortly after use of the substance.
The symptoms are not due to a general medical condition and are not better
accounted for by another mental disorder.
Substance Withdrawal
Substance withdrawal is the diagnosis used to describe a substance specific syndrome
that results from the abrupt cessation of heavy and prolonged use of a substance (e.g.,
opioid withdrawal). A general description of substance withdrawal requires the
following criteria to be met:
The development of a substance-specific syndrome due to the cessation of (or
reduction in) substance use that has been heavy and prolonged.
The substance-specific syndrome causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
The symptoms are not due to a general medical condition and are not better
accounted for by another mental disorder.
In the discussion of each substance in the sections that follow, the generic tables listed
above, derived from the DSM-5 can be applied. Thus, in place of the word substance, the
clinician should indicate the specific substance or drug that is used or that caused
intoxication or withdrawal.
TREATMENT AND REHABILITATION
Some persons who develop substance-related problems recover without formal
treatment, especially as they age. For those patients with less severe disorders, such as
nicotine addiction, relatively brief interventions are often as effective as more intensive
treatments. Because these brief interventions do not change the environment, alter druginduced brain changes, or provide new skills, a change in the patient’s motivation
(cognitive change) probably has the best impact on the drug-using behavior. For those
individuals who do not respond or whose dependence is more severe, a variety of
interventions described below appear to be effective.
It is useful to distinguish among specific procedures or techniques (e.g., individual
therapy, family therapy, group therapy, relapse prevention, and pharmacotherapy) and
treatment programs. Most programs use a number of specific procedures and involve
several professional disciplines as well as nonprofessionals who have special skills or
personal experience with the substance problem being treated. The best treatment
programs combine specific procedures and disciplines to meet the needs of the
individual patient after a careful assessment.
No classification system is generally accepted for either the specific procedures used in
treatment or programs using various combinations of procedures. This lack of
standardized terminology for categorizing procedures and programs presents a problem,
even when the field of interest is narrowed from substance problems in general to
treatment for a single substance, such as alcohol, tobacco, or cocaine. Except in
carefully monitored research projects, even the definitions of specific procedures (e.g.,
individual counseling, group therapy, and methadone maintenance) tend to be so
imprecise that usually just what transactions are supposed to occur cannot be inferred.
Nevertheless, for descriptive purposes, programs are often broadly grouped on the basis
of one or more of their salient characteristics: whether the program is aimed at merely
controlling acute withdrawal and consequences of recent drug use (detoxification) or is
focused on longer-term behavioral change; whether the program makes extensive use of
pharmacological interventions; and the degree to which the program is based on
individual psychotherapy, Alcoholics Anonymous (AA) or other 12-step principles, or
therapeutic community principles. For example, government agencies recently
categorized publicly funded treatment programs for drug dependence as (1) methadone
maintenance (mostly outpatient), (2) outpatient drug-free programs, (3) therapeutic
communities, or (4) short-term inpatient programs.
Selecting a Treatment
Not all interventions are applicable to all types of substance use or dependence, and
some of the more coercive interventions used for illicit drugs are not applicable to
substances that are legally available, such as tobacco. Addictive behaviors do not change
abruptly, but through a series of stages. Five stages in this gradual process have been
proposed: precontemplation, contemplation, preparation, action, and maintenance. For
some types of addictions the therapeutic alliance is enhanced when the treatment
approach is tailored to the patient’s stage of readiness to change. Interventions for some
drug use disorders may have a specific pharmacological agent as an important
component; for example, disulfiram, naltrexone (ReVia), or acamprosate for alcoholism;
methadone (Dolophine), levomethadyl acetate (ORLAAM), or buprenorphine (Buprenex)
for heroin addiction; and nicotine delivery devices or bupropion (Zyban) for tobacco
dependence. Not all interventions are likely to be useful to health care professionals. For
example, many youthful offenders with histories of drug use or dependence are now
remanded to special facilities (boot camps); other programs for offenders (and
sometimes for employees) rely almost exclusively on the deterrent effect of frequent
urine testing; and a third group are built around religious conversion or rededication in
a specific religious sect or denomination. In contrast to the numerous studies suggesting
some value for brief interventions for smoking and for problem drinking, few controlled
studies are conducted of brief interventions for those seeking treatment for dependence
on illicit drugs.
In general, brief interventions (e.g., a few weeks of detoxification, whether in or out
of a hospital) used for persons who are severely dependent on illicit opioids have
limited effect on outcome measured a few months later. Substantial reductions in illicit
drug use, antisocial behaviors, and psychiatric distress among patients dependent on
cocaine or heroin are much more likely following treatment lasting at least 3 months.
Such a time-in-treatment effect is seen across very different modalities, from residential
therapeutic communities to ambulatory methadone maintenance programs. Although
some patients appear to benefit from a few days or weeks of treatment, a substantial
percentage of users of illicit drugs drop out (or are dropped) from treatment before they
have achieved significant benefits.
Some of the variance in treatment outcomes can be attributed to differences in the
characteristics of patients entering treatment and by events and conditions following
treatment. Programs based on similar philosophical principles and using what seem to
be similar therapeutic procedures vary greatly in effectiveness, however. Some of the
differences among programs that seem to be similar reflect the range and intensity of
services offered. Programs with professionally trained staffs that provide more
comprehensive services to patients with more severe psychiatric difficulties are more
likely able to retain those patients in treatment and help them make positive changes.
Differences in the skills of individual counselors and professionals can strongly affect
outcomes.
Such generalizations concerning programs serving illicit drug users may not hold for
programs dealing with those seeking treatment for alcohol, tobacco, or even cannabis
problems uncomplicated by heavy use of illicit drugs. In such cases, relatively brief
periods of individual or group counseling can produce long-lasting reductions in drug
use. The outcomes usually considered in programs dealing with illicit drugs have
typically included measures of social functioning, employment, and criminal activity, as
well as decreased drug-using behavior.
Treatment of Comorbidity
Treatment of the severely mentally ill (primarily those with schizophrenia and
schizoaffective disorders) who are also drug dependent continues to pose problems for
clinicians. Although some special facilities have been developed that use both
antipsychotic drugs and therapeutic community principles, for the most part, specialized
addiction agencies have difficulty treating these patients. Generally, integrated
treatment in which the same staff can treat both the psychiatric disorder and the
addiction is more effective than either parallel treatment (a mental health and a
specialty addiction program providing care concurrently) or sequential treatment
(treating either the addiction or the psychiatric disorder first and then dealing with the
comorbid condition).
Services and Outcome
The extension of managed care into the public sector has produced a major reduction in
the use of hospital-based detoxification and virtual disappearance of residential
rehabilitation programs for alcoholics. Managed-care organizations, however, tend to
assume that the relatively brief courses of outpatient counseling that are effective with
private-sector alcoholic patients are also effective with patients who are dependent on
illicit drugs and who have minimal social supports. For the present, the trend is to
provide the care that costs the least over the short term and to ignore studies showing
that more services can produce better long-term outcomes.
Treatment is often a worthwhile social expenditure. For example, treatment of
antisocial illicit drug users in outpatient settings can decrease antisocial behavior and
reduce rates of human immunodeficiency virus (HIV) seroconversion that more than
offset the treatment cost. Treatment in a prison setting can decrease post-release costs
associated with drug use and rearrests. Despite such evidence, problems exist in
maintaining public support for treatment of substance dependence in both the public
and private sectors. This lack of support suggests that these problems continue to be
viewed, at least in part, as moral failings rather than as medical disorders.
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20.2 Alcohol-Related Disorders
Alcoholism is among the most common psychiatric disorders observed in the Western
world. Alcohol-related problems in the United States contribute to 2 million injuries each
year, including 22,000 deaths. Recent years have witnessed a blossoming of clinically
relevant research regarding alcohol abuse and dependence, including information on
specific genetic influences, the clinical course of these conditions, and the development
of new and helpful treatments.
Alcohol is a potent drug that causes both acute and chronic changes in almost all
neurochemical systems. Thus alcohol abuse can produce serious temporary psychological
symptoms including depression, anxiety, and psychoses. Long-term, escalating levels of
alcohol consumption can produce tolerance as well as such intense adaptation of the
body that cessation of use can precipitate a withdrawal syndrome usually marked by
insomnia, evidence of hyperactivity of the autonomic nervous system, and feelings of
anxiety. Therefore, in an adequate evaluation of life problems and psychiatric
symptoms in a patient, the clinician must consider the possibility that the clinical
situation reflects the effects of alcohol.
EPIDEMIOLOGY
Psychiatrists need to be concerned about alcoholism because this condition is common;
intoxication and withdrawal mimic many major psychiatric disorders, and the usual
person with alcoholism does not fit the stereotype (i.e., so called “nasty knock-down
drinkers”).
Prevalence of Drinking
At some time during life, 90 percent of the population in the United States drinks, with
most people beginning their alcohol intake in the early to middle teens (Table 20.2-1).
By the end of high school, 80 percent of students have consumed alcohol, and more than
60 percent have been intoxicated. At any time, two of three men are drinkers, with a
ratio of persisting alcohol intake of approximately 1.3 men to 1.0 women, and the
highest prevalence of drinking from the middle or late teens to the mid-20s.
Table 20.2-1
Alcohol Epidemiology
Men and women with higher education and income are most likely to imbibe, and,
among religious denominations, Jews have the highest proportion who consume alcohol
but among the lowest rates of alcohol dependence. Other ethnicities, such as the Irish,
have higher rates of severe alcohol problems, but they also have significantly higher
rates of abstentions. Some estimates show that more than 60 percent of men and women
in some Native American and Inuit tribes have been alcohol dependent at some time. In
the United States, the average adult consumes 2.2 gallons of absolute alcohol a year, a
decrease from 2.7 gallons per capita in 1981.
Drinking alcohol-containing beverages is generally considered an acceptable habit in
the United States. About 90 percent of all US residents have had an alcohol-containing
drink at least once in their lives, and about 51 percent of all US adults are current users
of alcohol. After heart disease and cancer, alcohol-related disorders constitute the third
largest health problem in the United States today. Beer accounts for about one half of all
alcohol consumption, liquor for about one third, and wine for about one sixth. About 30
to 45 percent of all adults in the United States have had at least one transient episode of
an alcohol-related problem, usually an alcohol-induced amnestic episode (e.g., a
blackout), driving a motor vehicle while intoxicated, or missing school or work because
of excessive drinking. About 10 percent of women and 20 percent of men have met the
diagnostic criteria for alcohol abuse during their lifetimes, and 3 to 5 percent of women
and 10 percent of men have met the diagnostic criteria for the more serious diagnosis of
alcohol dependence during their lifetimes. About 200,000 deaths each year are directly
related to alcohol abuse. The common causes of death among persons with the alcoholrelated disorders are suicide, cancer, heart disease, and hepatic disease. Although
persons involved in automotive fatalities do not always meet the diagnostic criteria for
an alcohol-related disorder, drunk drivers are involved in about 50 percent of all
automotive fatalities, and this percentage increases to about 75 percent when only
accidents occurring in the late evening are considered. Alcohol use and alcohol-related
disorders are associated with about 50 percent of all homicides and 25 percent of all
suicides. Alcohol abuse reduces life expectancy by about 10 years, and alcohol leads all
other substances in substance-related deaths. Table 20.2-2 lists other epidemiological
data about alcohol use.
Table 20.2-2
Epidemiological Data for Alcohol-Related Disorders
COMORBIDITY
The psychiatric diagnoses most commonly associated with the alcohol-related disorders
are other substance-related disorders, antisocial personality disorder, mood disorders,
and anxiety disorders. Although the data are somewhat controversial, most suggest that
persons with alcohol-related disorders have a markedly higher suicide rate than the
general population.
Antisocial Personality Disorder
A relation between antisocial personality disorder and alcohol-related disorders has frequently been reported. Some studies
suggest that antisocial personality disorder is particularly common in men with an alcohol-related disorder and can
precede the development of the alcohol-related disorder. Other studies, however, suggest that antisocial personality
disorder and alcohol-related disorders are completely distinct entities that are not causally related.
Mood Disorders
About 30 to 40 percent of persons with an alcohol-related disorder meet the diagnostic criteria for major depressive
disorder sometime during their lifetimes. Depression is more common in women than in men with these disorders. Several
studies reported that depression is likely to occur in patients with alcohol-related disorders who have a high daily
consumption of alcohol and a family history of alcohol abuse. Persons with alcohol-related disorders and major depressive
disorder are at great risk for attempting suicide and are likely to have other substance-related disorder diagnoses. Some
clinicians recommend antidepressant drug therapy for depressive symptoms that remain after 2 to 3 weeks of sobriety.
Patients with bipolar I disorder are thought to be at risk for developing an alcohol-related disorder; they may use alcohol
to self-medicate their manic episodes. Some studies have shown that persons with both alcohol-related disorder and
depressive disorder diagnoses have concentrations of dopamine metabolites (homovanillic acid) and γ-aminobutyric acid
(GABA) in their cerebrospinal fluid (CSF).
Anxiety Disorders
Many persons use alcohol for its efficacy in alleviating anxiety. Although the comorbidity between alcohol-related
disorders and mood disorders is fairly widely recognized, it is less well known that perhaps 25 to 50 percent of all persons
with alcohol-related disorders also meet the diagnostic criteria for an anxiety disorder. Phobias and panic disorder are
particularly frequent comorbid diagnoses in these patients. Some data indicate that alcohol may be used in an attempt to
self-medicate symptoms of agoraphobia or social phobia, but an alcohol-related disorder is likely to precede the
development of panic disorder or generalized anxiety disorder.
Suicide
Most estimates of the prevalence of suicide among persons with alcohol-related disorders range from 10 to 15 percent,
although alcohol use itself may be involved in a much higher percentage of suicides. Some investigators have questioned
whether the suicide rate among persons with alcohol-related disorders is as high as the numbers suggest. Factors that have
been associated with suicide among persons with alcohol-related disorders include the presence of a major depressive
episode, weak psychosocial support systems, a serious coexisting medical condition, unemployment, and living alone.
ETIOLOGY
Many factors affect the decision to drink, the development of temporary alcohol-related
difficulties in the teenage years and the 20s, and the development of alcohol
dependence. The initiation of alcohol intake probably depends largely on social,
religious, and psychological factors, although genetic characteristics might also
contribute. The factors that influence the decision to drink or those that contribute to
temporary problems might differ, however, from those that add to the risk for the
severe, recurring problems of alcohol dependence.
A similar interplay between genetic and environmental influences contributes to
many medical and psychiatric conditions, and, thus, a review of these factors in
alcoholism offers information about complex genetic disorders overall. Dominant or
recessive genes, although important, explain only relatively rare conditions. Most
disorders have some level of genetic predisposition that usually relates to a series of
different genetically influenced characteristics, each of which increases or decreases the
risk for the disorder.
It is likely that a series of genetic influences combine to explain approximately 60
percent of the proportion of risk for alcoholism, with environment responsible for the
remaining proportion of the variance. The divisions offered in this section, therefore,
are more heuristic than real, because it is the combination of a series of psychological,
sociocultural, biological, and other factors that are responsible for the development of
severe, repetitive alcohol-related life problems.
Psychological Theories
A variety of theories relate to the use of alcohol to reduce tension, increase feelings of power, and decrease the effects of
psychological pain. Perhaps the greatest interest has been paid to the observation that people with alcohol-related
problems often report that alcohol decreases their feelings of nervousness and helps them cope with the day-to-day stresses
of life. The psychological theories are built, in part, on the observation among nonalcoholic people that the intake of low
doses of alcohol in a tense social setting or after a difficult day can be associated with an enhanced feeling of well-being and
an improved ease of interactions. In high doses, especially at falling blood alcohol levels, however, most measures of
muscle tension and psychological feelings of nervousness and tension are increased. Thus, tension-reducing effects of this
drug might have an impact most on light to moderate drinkers or add to the relief of withdrawal symptoms, but play a
minor role in causing alcoholism. The theories that focus on alcohol’s potential to enhance feelings of being powerful and
sexually attractive and to decrease the effects of psychological pain are difficult to evaluate definitively.
Psychodynamic Theories
Perhaps related to the disinhibiting or anxiety-lowering effects of lower doses of alcohol is the hypothesis that some
people may use this drug to help them deal with self-punitive harsh superegos and to decrease unconscious stress levels.
In addition, classic psychoanalytical theory hypothesizes that at least some alcoholic people may have become fixated at
the oral stage of development and use alcohol to relieve their frustrations by taking the substance by mouth. Hypotheses
regarding arrested phases of psychosexual development, although heuristically useful, have had little effect on the usual
treatment approaches and are not the focus of extensive ongoing research. Similarly, most studies have not been able to
document an “addictive personality” present in most alcoholics and associated with a propensity to lack control of intake
of a wide range of substances and foods. Although pathological scores on personality tests are often seen during
intoxication, withdrawal, and early recovery, many of these characteristics are not found to predate alcoholism, and most
disappear with abstinence. Similarly, prospective studies of children of alcoholics who themselves have no co-occurring
disorders usually document high risks mostly for alcoholism. As is described later in this text, one partial exception occurs
with the extreme levels of impulsivity seen in the 15 to 20 percent of alcoholic men with antisocial personality disorder,
because they have high risks for criminality, violence, and multiple substance dependencies.
Behavioral Theories
Expectations about the rewarding effects of drinking, cognitive attitudes toward responsibility for one’s behavior, and
subsequent reinforcement after alcohol intake all contribute to the decision to drink again after the first experience with
alcohol and to continue to imbibe despite problems. These issues are important in efforts to modify drinking behaviors in
the general population, and they contribute to some important aspects of alcoholic rehabilitation.
Sociocultural Theories
Sociocultural theories are often based on extrapolations from social groups that have high and low rates of alcoholism.
Theorists hypothesize that ethnic groups, such as Jews, who introduce children to modest levels of drinking in a family
atmosphere and eschew drunkenness have low rates of alcoholism. Some other groups, such as Irish men or some
American Indian tribes with high rates of abstention but a tradition of drinking to the point of drunkenness among
drinkers, are believed to have high rates of alcoholism. These theories, however, often depend on stereotypes that tend to
be erroneous, and prominent exceptions to these rules exist. For example, some theories based on observations of the Irish
and the French have incorrectly predicted high rates of alcoholism among the Italians.
Yet, environmental events, presumably including cultural factors, account for as much as 40 percent of the alcoholism
risk. Thus, although these are difficult to study, it is likely that cultural attitudes toward drinking, drunkenness, and
personal responsibility for consequences are important contributors to the rates of alcohol-related problems in a society. In
the final analysis, social and psychological theories are probably highly relevant, because they outline factors that
contribute to the onset of drinking, the development of temporary alcohol-related life difficulties, and even alcoholism.
The problem is how to gather relatively definitive data to support or refute the theories.
Childhood History
Researchers have identified several factors in the childhood histories of persons with
later alcohol-related disorders and in children at high risk for having an alcohol-related
disorder because one or both of their parents are affected. In experimental studies,
children at high risk for alcohol-related disorders have been found to possess, on
average, a range of deficits on neurocognitive testing, low amplitude of the P300 wave
on evoked potential testing, and a variety of abnormalities on electroencephalography
(EEG) recordings. Studies of high-risk offspring in their 20s have also shown a generally
blunted effect of alcohol compared with that seen in persons whose parents have not
been diagnosed with alcohol-related disorder. These findings suggest that a heritable
biological brain function may predispose a person to an alcohol-related disorder. A
childhood history of attention-deficit/hyperactivity disorder (ADHD), conduct disorder,
or both, increases a child’s risk for an alcohol-related disorder as an adult. Personality
disorders, especially antisocial personality disorder, as noted earlier, also predispose a
person to an alcohol-related disorder.
Genetic Theories
Importance of Genetic Influences.
Four lines of evidence support the
conclusion that alcoholism is genetically influenced. First, a threefold to fourfold
increased risk for severe alcohol problems is seen in close relatives of alcoholic people.
The rate of alcohol problems increases with the number of alcoholic relatives, the
severity of their illness, and the closeness of their genetic relationship to the person
under study. The family investigations do little to separate the importance of genetics
and environment, and the second approach, twin studies, takes the data a step further.
The rate of similarity, or concordance, for severe alcohol-related problems is
significantly higher in identical twins of alcoholic individuals than in fraternal twins in
most investigations, which estimate that genes explain 60 percent of the variance, with
the remainder relating to nonshared, probably adult environmental influences. Third,
the adoption-type studies have all revealed a significantly enhanced risk for alcoholism
in the offspring of alcoholic parents, even when the children had been separated from
their biological parents close to birth and raised without any knowledge of the problems
within the biological family. The risk for severe alcohol-related difficulties is not further
enhanced by being raised by an alcoholic adoptive family. Finally, studies in animals
support the importance of a variety of yet-to-be-identified genes in the free-choice use of
alcohol, subsequent levels of intoxication, and some consequences.
EFFECTS OF ALCOHOL
The term alcohol refers to a large group of organic molecules that have a hydroxyl group
(-OH) attached to a saturated carbon atom. Ethyl alcohol, also called ethanol, is the
common form of alcohol; sometimes referred to as beverage alcohol, ethyl alcohol is used
for drinking. The chemical formula for ethanol is CH3-CH2-OH.
The characteristic tastes and flavors of alcohol-containing beverages result from their methods of production, which
produce various congeners in the final product, including methanol, butanol, aldehydes, phenols, tannins, and trace
amounts of various metals. Although the congeners may confer some differential psychoactive effects on the various
alcohol-containing beverages, these differences are minimal compared with the effects of ethanol itself. A single drink is
usually considered to contain about 12 g of ethanol, which is the content of 12 ounces of beer (7.2 proof, 3.6 percent
ethanol in the United States), one 4-ounce glass of nonfortified wine, or 1 to 1.5 ounces of an 80-proof (40 percent ethanol)
liquor (e.g., whiskey or gin). In calculating patients’ alcohol intake, however, clinicians should be aware that beers vary in
their alcohol content, that beers are available in small and large cans and mugs, that glasses of wine range from 2 to 6
ounces, and that mixed drinks at some bars and in most homes contain 2 to 3 ounces of liquor. Nonetheless, using the
moderate sizes of drinks, clinicians can estimate that a single drink increases the blood alcohol level of a 150-pound man by
15 to 20 mg/dL, which is about the concentration of alcohol that an average person can metabolize in 1 hour.
The possible beneficial effects of alcohol have been publicized, especially by the makers and the distributors of alcohol.
Most attention has been focused on some epidemiological data that suggest that one or two glasses of red wine each day
lower the incidence of cardiovascular disease; these findings, however, are highly controversial.
Absorption
About 10 percent of consumed alcohol is absorbed from the stomach, and the remainder from the small intestine. Peak
blood concentration of alcohol is reached in 30 to 90 minutes and usually in 45 to 60 minutes, depending on whether the
alcohol was ingested on an empty stomach (which enhances absorption) or with food (which delays absorption). The time
to peak blood concentration also depends on the time during which the alcohol was consumed; rapid drinking reduces the
time to peak concentration, slower drinking increases it. Absorption is most rapid with beverages containing 15 to 30
percent alcohol (30 to 60 proof). There is some dispute about whether carbonation (e.g., in champagne and in drinks
mixed with seltzer) enhances the absorption of alcohol.
The body has protective devices against inundation by alcohol. For example, if the concentration of alcohol in the
stomach becomes too high, mucus is secreted and the pyloric valve closes. These actions slow the absorption and keep the
alcohol from passing into the small intestine, where there are no significant restraints on absorption. Thus, a large amount
of alcohol can remain unabsorbed in the stomach for hours. Furthermore, pylorospasm often results in nausea and
vomiting.
Once alcohol is absorbed into the bloodstream, it is distributed to all body tissues. Because alcohol is uniformly
dissolved in the body’s water, tissues containing a high proportion of water receive a high concentration of alcohol. The
intoxicating effects are greater when the blood alcohol concentration is rising than when it is falling (the Mellanby effects).
For this reason, the rate of absorption bears directly on the intoxication response.
Metabolism
About 90 percent of absorbed alcohol is metabolized through oxidation in the liver; the remaining 10 percent is excreted
unchanged by the kidneys and lungs. The rate of oxidation by the liver is constant and independent of the body’s energy
requirements. The body can metabolize about 15 mg/dL per hour, with a range of 10 to 34 mg/dL per hour. That is, the
average person oxidizes three fourths of an ounce of 40 percent (80 proof) alcohol in an hour. In persons with a history of
excessive alcohol consumption, upregulation of the necessary enzymes results in rapid alcohol metabolism.
Alcohol is metabolized by two enzymes: alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. ADH catalyzes the
conversion of alcohol into acetaldehyde, which is a toxic compound; aldehyde dehydrogenase catalyzes the conversion of
acetaldehyde into acetic acid. Aldehyde dehydrogenase is inhibited by disulfiram (Antabuse), often used in the treatment
of alcohol-related disorders. Some studies have shown that women have a lower ADH blood content than men; this fact
may account for woman’s tendency to become more intoxicated than men after drinking the same amount of alcohol. The
decreased function of alcohol-metabolizing enzymes in some Asian persons can also lead to easy intoxication and toxic
symptoms.
Effects on the Brain
Biochemistry.
In contrast to most other substances of abuse with identified
receptor targets—such as the N-methyl-D-aspartate (NMDA) receptor of phencyclidine
(PCP)—no single molecular target has been identified as the mediator for the effects of
alcohol. The longstanding theory about the biochemical effects of alcohol concerns its
effects on the membranes of neurons. Data support the hypothesis that alcohol produces
its effects by intercalating itself into membranes and, thus, increasing fluidity of the
membranes with short-term use. With long-term use, however, the theory hypothesizes
that the membranes become rigid or stiff. The fluidity of the membranes is critical to
normal functioning of receptors, ion channels, and other membrane-bound functional
proteins. In recent studies, researchers have attempted to identify specific molecular
targets for the effects of alcohol. Most attention has been focused on the effects of
alcohol at ion channels. Specifically, studies have found that alcohol ion channel
activities associated with the nicotinic acetylcholine, serotonin 5-hydroxytryptamine3
(5-HT3), and GABA type A (GABAA) receptors are enhanced by alcohol, whereas ion
channel activities associated with glutamate receptors and voltage-gated calcium
channels are inhibited.
Behavioral Effects.
As the net result of the molecular activities, alcohol functions
as a depressant much like the barbiturates and the benzodiazepines, with which alcohol
has some cross-tolerance and cross-dependence. At a level of 0.05 percent alcohol in the
blood, thought, judgment, and restraint are loosened and sometimes disrupted. At a
concentration of 0.1 percent, voluntary motor actions usually become perceptibly
clumsy. In most states, legal intoxication ranges from 0.1 to 0.15 percent blood alcohol
level. At 0.2 percent, the function of the entire motor area of the brain is measurably
depressed, and the parts of the brain that control emotional behavior are also affected.
At 0.3 percent, a person is commonly confused or may become stuporous; at 0.4 to 0.5
percent, the person falls into a coma. At higher levels, the primitive centers of the brain
that control breathing and heart rate are affected, and death ensues secondary to direct
respiratory depression or the aspiration of vomitus. Persons with long-term histories of
alcohol abuse, however, can tolerate much higher concentrations of alcohol than can
alcohol-naïve persons; their alcohol tolerance may cause them to falsely appear less
intoxicated than they really are.
Sleep Effects.
Although alcohol consumed in the evening usually increases the ease
of falling asleep (decreased sleep latency), alcohol also has adverse effects on sleep
architecture. Specifically, alcohol use is associated with a decrease in rapid eye
movement sleep (REM or dream sleep) and deep sleep (stage 4) and more sleep
fragmentation, with more and longer episodes of awakening. Therefore, the idea that
drinking alcohol helps persons fall asleep is a myth.
Other Physiological Effects
Liver.
The major adverse effects of alcohol use are related to liver damage. Alcohol
use, even as short as week-long episodes of increased drinking, can result in an
accumulation of fats and proteins, which produce the appearance of a fatty liver,
sometimes found on physical examination as an enlarged liver. The association between
fatty infiltration of the liver and serious liver damage remains unclear. Alcohol use,
however, is associated with the development of alcoholic hepatitis and hepatic cirrhosis.
Gastrointestinal System.
Long-term heavy drinking is associated with developing
esophagitis, gastritis, achlorhydria, and gastric ulcers. The development of esophageal
varices can accompany particularly heavy alcohol abuse; the rupture of the varices is a
medical emergency often resulting in death by exsanguination. Disorders of the small
intestine occasionally occur, and pancreatitis, pancreatic insufficiency, and pancreatic
cancer are also associated with heavy alcohol use. Heavy alcohol intake can interfere
with the normal processes of food digestion and absorption; as a result, consumed food
is inadequately digested. Alcohol abuse also appears to inhibit the intestine’s capacity to
absorb various nutrients, such as vitamins and amino acids. This effect, coupled with the
often poor dietary habits of those with alcohol-related disorders, can cause serious
vitamin deficiencies, particularly of the B vitamins.
Other Bodily Systems.
Significant intake of alcohol has been associated with
increased blood pressure, dysregulation of lipoprotein and triglyceride metabolism, and
increased risk for myocardial infarction and cerebrovascular disease. Alcohol has been
shown to affect the hearts of nonalcoholic persons who do not usually drink, increasing
the resting cardiac output, the heart rate, and the myocardial oxygen consumption.
Evidence indicates that alcohol intake can adversely affect the hematopoietic system
and can increase the incidence of cancer, particularly head, neck, esophageal, stomach,
hepatic, colonic, and lung cancer. Acute intoxication may also be associated with
hypoglycemia, which, when unrecognized, may be responsible for some of the sudden
deaths of persons who are intoxicated. Muscle weakness is another side effect of
alcoholism. Recent evidence shows that alcohol intake raises the blood concentration of
estradiol in women. The increase in estradiol correlates with the blood alcohol level.
Laboratory Tests.
The adverse effects of alcohol appear in common laboratory
tests, which can be useful diagnostic aids in identifying persons with alcohol-related
disorders. The γ-glutamyl transpeptidase levels are high in about 80 percent of those
with alcohol-related disorders, and the mean corpuscular volume (MCV) is high in about
60 percent, more so in women than in men. Other laboratory test values that may be
high in association with alcohol abuse are those of uric acid, triglycerides, aspartate
aminotransferase (AST), and alanine aminotransferase (ALT).
Drug Interactions
The interaction between alcohol and other substances can be dangerous, even fatal.
Certain substances, such as alcohol and phenobarbital (Luminal), are metabolized by the
liver, and their prolonged use can lead to acceleration of their metabolism. When
persons with alcohol-related disorders are sober, this accelerated metabolism makes
them unusually tolerant to many drugs such as sedatives and hypnotics; when they are
intoxicated, however, these drugs compete with the alcohol for the same detoxification
mechanisms, and potentially toxic concentrations of all involved substances can
accumulate in the blood.
The effects of alcohol and other central nervous system (CNS) depressants are usually
synergistic. Sedatives, hypnotics, and drugs that relieve pain, motion sickness, head
colds, and allergy symptoms must be used with caution by persons with alcohol-related
disorders. Narcotics depress the sensory areas of the cerebral cortex and can produce
pain relief, sedation, apathy, drowsiness, and sleep; high doses can result in respiratory
failure and death. Increasing the dosages of sedative-hypnotic drugs, such as chloral
hydrate (Noctec) and benzodiazepines, especially when they are combined with alcohol,
produces a range of effects from sedation to motor and intellectual impairment to
stupor, coma, and death. Because sedatives and other psychotropic drugs can potentiate
the effects of alcohol, patients should be instructed about the dangers of combining CNS
depressants and alcohol, particularly when they are driving or operating machinery.
DISORDERS
Alcohol Use Disorder
Diagnosis and Clinical Features.
In the fifth edition of Diagnostic and Statistical
Manual of Mental Disorders (DSM-5), all substance use disorders use the same general
criteria for dependence and abuse (see Section 20.1). A need for daily use of large
amounts of alcohol for adequate functioning, a regular pattern of heavy drinking
limited to weekends, and long periods of sobriety interspersed with binges of heavy
alcohol intake lasting for weeks or months strongly suggest alcohol dependence and
alcohol abuse. The drinking patterns are often associated with certain behaviors: the
inability to cut down or stop drinking; repeated efforts to control or reduce excessive
drinking by “going on the wagon” (periods of temporary abstinence) or by restricting
drinking to certain times of the day; binges (remaining intoxicated throughout the day
for at least 2 days); occasional consumption of a fifth of spirits (or its equivalent in wine
or beer); amnestic periods for events occurring while intoxicated (blackouts); the
continuation of drinking despite a serious physical disorder that the person knows is
exacerbated by alcohol use; and drinking nonbeverage alcohol, such as fuel and
commercial products containing alcohol. In addition, persons with alcohol dependence
and alcohol abuse show impaired social or occupational functioning because of alcohol
use (e.g., violence while intoxicated, absence from work, job loss), legal difficulties
(e.g., arrest for intoxicated behavior and traffic accidents while intoxicated), and
arguments or difficulties with family members or friends about excessive alcohol
consumption.
Mark, a 45-year-old divorced man, was examined in a hospital emergency room
because he had been confused and unable to care for himself of the preceding 3 days.
His brother, who brought him to the hospital, reported that the patient has consumed
large quantities of beer and wine daily for more than 5 years. His home and job lives
were reasonably stable until his divorce 5 years prior. The brother indicated that
Mark’s drinking pattern since the divorce has been approximately 5 beers and a
fourth of wine a day. Mark often experienced blackouts from drinking and missed
days of work frequently. As a result, Mark has lost several jobs in the past 5 years.
Although he usually provides for himself marginally with small jobs, 3 days earlier he
ran out of money and alcohol and resorted to panhandling on the streets for cash to
buy food. Mark had been poorly nourished, having one meal per day at best and was
evidently relying on beer as his prime source of nourishment.
On examination, Mark alternates between apprehension and chatty, superficial
warmth. He is pretty keyed up and talks constantly in a rambling and unfocused
manner. His recognition of the physician varies; at times he recognizes him and other
times he becomes confused and believes the doctor to be his other brother who lives in
another state. On two occasions he referred to the physician by said brother’s name
and asked when he arrived in town, evidently having lost track of the interview up to
that point. He has a gross hand tremor at rest and is disoriented to time. He believes
he’s in a parking lot rather than a hospital. Efforts at memory and calculation testing
fail because Mark’s attention shifts so rapidly.
Subtypes of Alcohol Dependence.
Various researchers have attempted to divide
alcohol dependence into subtypes based primarily on phenomenological characteristics.
One recent classification notes that type A alcohol dependence is characterized by late
onset, few childhood risk factors, relatively mild dependence, few alcohol-related
problems, and little psychopathology. Type B alcohol dependence is characterized by
many childhood risk factors, severe dependence, an early onset of alcohol-related
problems, much psychopathology, a strong family history of alcohol abuse, frequent
polysubstance abuse, a long history of alcohol treatment, and a lot of severe life
stresses. Some researchers have found that type A persons who are alcohol dependent
may respond to interactional psychotherapies, whereas type B persons who are alcohol
dependent may respond to training in coping skills.
Other subtyping schemes of alcohol dependence have received fairly wide recognition
in the literature. One group of investigators proposed three subtypes: earlystage
problem drinkers, who do not yet have complete alcohol dependence syndromes;
affiliative drinkers, who tend to drink daily in moderate amounts in social settings; and
schizoid-isolated drinkers, who have severe dependence and tend to drink in binges and
often alone.
Another investigator described gamma alcohol dependence, which is thought to be
common in the United States and represents the alcohol dependence seen in those who
are active in Alcoholics Anonymous (AA). This variant concerns control problems in
which persons are unable to stop drinking once they start. When drinking is terminated
as a result of ill health or lack of money, these persons can abstain for varying periods.
In delta alcohol dependence, perhaps more common in Europe than in the United
States, persons who are alcohol dependent must drink a certain amount each day but
are unaware of a lack of control. The alcohol use disorder may not be discovered until a
person who must stop drinking for some reason exhibits withdrawal symptoms.
Another researcher has suggested a type I, male-limited variety of alcohol dependence,
characterized by late onset, more evidence of psychological than of physical
dependence, and the presence of guilt feelings. Type II, male-limited alcohol dependence
is characterized by onset at an early age, spontaneous seeking of alcohol for
consumption, and a socially disruptive set of behaviors when intoxicated.
Four subtypes of alcoholism were postulated by still another investigator. The first is
antisocial alcoholism, typically with a predominance in men, a poor prognosis, early
onset of alcohol-related problems, and a close association with antisocial personality
disorder. The second is developmentally cumulative alcoholism, with a primary tendency
for alcohol abuse that is exacerbated with time as cultural expectations foster increased
opportunities to drink. The third is negative-affect alcoholism, which is more common in
women than in men; according to this hypothesis, women are likely to use alcohol for
mood regulation and to help ease social relationships. The fourth is developmentally
limited alcoholism, with frequent bouts of consuming large amounts of alcohol; the bouts
become less frequent as persons age and respond to the increased expectations of
society about their jobs and families.
Alcohol Intoxication
The DSM-5 diagnostic criteria for alcohol intoxication (also called simple drunkenness)
are based on evidence of recent ingestion of ethanol, maladaptive behavior, and at least
one of several possible physiological correlates of intoxication (Table 20.2-3). As a
conservative approach to identifying blood levels that are likely to have major effects
on driving abilities, the legal definition of intoxication in most states in the United
States requires a blood concentration of 80 or 100 mg ethanol per deciliter of blood
(mg/dL), which is the same as 0.08 to 0.10 g/dL. The following is an outline of the
rough estimates of the levels of impairment likely to be seen at various blood alcohol
concentrations, for most people. Evidence of behavioral changes, a slowing in motor
performance, and a decrease in the ability to think clearly occurs at doses as low as 20
to 30 mg/dL, as shown in Table 20.2-4. Blood concentrations between 100 and 200
mg/dL are likely to increase the impairment in coordination and judgment to severe
problems with coordination (ataxia), increasing lability of mood, and progressively
greater levels of cognitive deterioration. Anyone who does not show significant levels of
impairment in motor and mental performance at approximately 150 mg/dL probably
has significant pharmacodynamic tolerance. In that range, most people without
significant tolerance also experience relatively severe nausea and vomiting. With blood
alcohol concentrations in the 200 to 300 mg/dL range, the slurring of speech is likely to
become more intense, and memory impairment (anterograde amnesia or alcoholic
blackouts) becomes pronounced. Further increases in blood alcohol concentration result
in the first level of anesthesia, and the nontolerant person who reaches 400 mg/dL or
more risks respiratory failure, coma, and death.
Table 20.2-3
Signs of Alcohol Intoxication
Table 20.2-4
Impairment Likely to be Seen at Different Blood Alcohol Concentrations
Alcohol Withdrawal
Alcohol withdrawal, even without delirium, can be serious; it can include seizures and
autonomic hyperactivity. Conditions that may predispose to, or aggravate, withdrawal
symptoms include fatigue, malnutrition, physical illness, and depression. The DSM-5
criteria for alcohol withdrawal require the cessation or reduction of alcohol use that was
heavy and prolonged as well as the presence of specific physical or neuropsychiatric
symptoms. The diagnosis also allows for the specification “with perceptual
disturbances.” One positron emission tomography (PET) study of blood flow during
alcohol withdrawal in otherwise healthy persons with alcohol dependence reported a
globally low rate of metabolic activity, although, with further inspection of the data, the
authors concluded that activity was especially low in the left parietal and right frontal
areas.
The classic sign of alcohol withdrawal is tremulousness, although the spectrum of
symptoms can expand to include psychotic and perceptual symptoms (e.g., delusions
and hallucinations), seizures, and the symptoms of delirium tremens (DTs), called
alcohol delirium in DSM-5. Tremulousness (commonly called the “shakes” or the
“jitters”) develops 6 to 8 hours after the cessation of drinking, the psychotic and
perceptual symptoms begin in 8 to 12 hours, seizures in 12 to 24 hours, and DTs
anytime during the first 72 hours, although physicians should watch for the development
of DTs for the first week of withdrawal. The syndrome of withdrawal sometimes skips
the usual progression and, for example, goes directly to DTs.
The tremor of alcohol withdrawal can be similar to either physiological tremor, with a
continuous tremor of great amplitude and of more than 8 Hz, or familial tremor, with
bursts of tremor activity slower than 8 Hz. Other symptoms of withdrawal include
general irritability, gastrointestinal symptoms (e.g., nausea and vomiting), and
sympathetic autonomic hyperactivity, including anxiety, arousal, sweating, facial
flushing, mydriasis, tachycardia, and mild hypertension. Patients experiencing alcohol
withdrawal are generally alert but may startle easily.
Twenty-nine-year-old Mr. F had been a heavy drinker for 8 years. One evening
after work, he started drinking with friends and drank throughout the evening. He fell
asleep in the early morning hours and upon awakening had a strong desire to drink
and decided not to attend work. He had several Bloody Marys instead of food because
food did not appeal to him. He went to a local bar in the afternoon and consumed
large quantities of beer. That evening he met with some friends and continued to
drink.
This drinking pattern continued for the next week. The beginning of the following
week he attempted to have a cup of coffee and found that he hands were shaking so
much that he could not get the cup to his mouth to drink. He eventually managed to
pour himself some wine in a glass and drank as much as he could. His hands then
became less shaky, but he now felt nauseous and began having dry heaves. He tried to
drink repeatedly but he could not keep the alcohol down. He felt very ill and anxious
so he contacted his physician who recommended he report to a hospital.
Upon evaluation, Mr. F was alert. He had a marked resting and intention tremor of
the hands, and his tongue and eyelids were tremulous. He was oriented and had no
memory impairment. When inquired about his drinking, Mr. F admits to drinking
several drinks each day for the past 8 years, but claims that his drinking never
interfered with his work or his relations with colleagues or friends. He denies having
any aftereffects from his drinking other than mild hangovers. He denies ever having a
binge such as this before and denies ever needing to drink daily in order to function
adequately. He admits, however, that he has never tried to reduce or stop drinking.
Withdrawal Seizures.
Seizures associated with alcohol withdrawal are
stereotyped, generalized, and tonic–clonic in character. Patients often have more than
one seizure 3 to 6 hours after the first seizure. Status epilepticus is relatively rare and
occurs in less than 3 percent of patients. Although anticonvulsant medications are not
required in the management of alcohol withdrawal seizures, the cause of the seizures is
difficult to establish when a patient is first assessed in the emergency room; thus, many
patients with withdrawal seizures receive anticonvulsant medications, which are then
discontinued once the cause of the seizures is recognized. Seizure activity in patients
with known alcohol abuse histories should still prompt clinicians to consider other
causative factors, such as head injuries, CNS infections, CNS neoplasms, and other
cerebrovascular diseases; long-term severe alcohol abuse can result in hypoglycemia,
hyponatremia, and hypomagnesemia—all of which can also be associated with seizures.
Treatment.
The primary medications to control alcohol withdrawal symptoms are
the benzodiazepines (Table 20.2-5). Many studies have found that benzodiazepines help
control seizure activity, delirium, anxiety, tachycardia, hypertension, diaphoresis, and
tremor associated with alcohol withdrawal. Benzodiazepines can be given either orally
or parenterally; neither diazepam (Valium) nor chlordiazepoxide (Librium), however,
should be given intramuscularly (IM) because of their erratic absorption by this route.
Clinicians must titrate the dosage of the benzodiazepine, starting with a high dosage
and lowering the dosage as the patient recovers. Sufficient benzodiazepines should be
given to keep patients calm and sedated but not so sedated that they cannot be aroused
for clinicians to perform appropriate procedures, including neurological examinations.
Table 20.2-5
Drug Therapy for Alcohol Intoxication and Withdrawal
Although benzodiazepines are the standard treatment for alcohol withdrawal, studies
have shown that carbamazepine (Tegretol) in daily doses of 800 mg is as effective as
benzodiazepines and has the added benefit of minimal abuse liability. Carbamazepine
use is gradually becoming common in the United States and Europe. The β-adrenergic
receptor antagonists and clonidine (Catapres) have also been used to block the
symptoms of sympathetic hyperactivity, but neither drug is an effective treatment for
seizures or delirium.
Delirium
Diagnosis and Clinical Features.
Patients with recognized alcohol withdrawal
symptoms should be carefully monitored to prevent progression to alcohol withdrawal
delirium, the most severe form of the withdrawal syndrome, also known as DTs. Alcohol
withdrawal delirium is a medical emergency that can result in significant morbidity and
mortality. Patients with delirium are a danger to themselves and to others. Because of
the unpredictability of their behavior, patients with delirium may be assaultive or
suicidal or may act on hallucinations or delusional thoughts as if they were genuine
dangers. Untreated, DTs has a mortality rate of 20 percent, usually as a result of an
intercurrent medical illness such as pneumonia, renal disease, hepatic insufficiency, or
heart failure. Although withdrawal seizures commonly precede the development of
alcohol withdrawal delirium, delirium can also appear unheralded. The essential feature
of the syndrome is delirium occurring within 1 week after a person stops drinking or
reduces the intake of alcohol. In addition to the symptoms of delirium, the features of
alcohol intoxication delirium include autonomic hyperactivity such as tachycardia,
diaphoresis, fever, anxiety, insomnia, and hypertension; perceptual distortions, most
frequently visual or tactile hallucinations; and fluctuating levels of psychomotor
activity, ranging from hyperexcitability to lethargy.
About 5 percent of persons with alcohol-related disorders who are hospitalized have
DTs. Because the syndrome usually develops on the third hospital day, a patient
admitted for an unrelated condition may unexpectedly have an episode of delirium, the
first sign of a previously undiagnosed alcohol-related disorder. Episodes of DTs usually
begin in a patient’s 30s or 40s after 5 to 15 years of heavy drinking, typically of the
binge type. Physical illness (e.g., hepatitis or pancreatitis) predisposes to the syndrome;
a person in good physical health rarely has DTs during alcohol withdrawal.
Mr. R, a 40-year-old man, was admitted to the orthopedic department of a general
hospital after experiencing a fall down stairs and breaking his leg. On the third day of
his hospital stay, he became increasingly nervous and started to tremble. He was
unable to sleep at night, talked incoherently, and was obviously very anxious. Mr. R,
when asked, denied an alcohol problem other than an occasional glass of wine.
When asked directly, his wife admitted that Mr. R drank large quantities of wine for
over 4 years. During the previous year, his drinking would begin every evening when
he came home from work and would not end until he fell asleep. On the evening of
admittance, the fall occurred before he was able to consume any alcohol.
During the few weeks prior to his admittance, Mr. R had eaten very little. On
several occasions, Mrs. R noticed that Mr. R was unable to recall even important
events from the previous day. He had a car accident 3 years prior but without major
injury. Mr. R had no other major health problems. His relationship with Mrs. R
became very difficult after he began drinking and Mrs. R was seriously contemplating
divorce. Mr. R had a tense relationship with his four children and he often argued
with them. Recently, the children tried to avoid Mr. R as much as possible.
On examination, Mr. R’s speech was rambling and incoherent. He believed that he
was still at work and that he had a job to finish. At times he thought the physicians
and nurses were his co-workers. At times he picked at bugs that he could see on his
bed sheets. He was disoriented in time and was startled easily by sounds from outside
the room. He sweat profusely and could not hold a glass without spilling some of the
contents.
Treatment.
The best treatment for DTs is prevention. Patients withdrawing from
alcohol who exhibit withdrawal phenomena should receive a benzodiazepine, such as 25
to 50 mg of chlordiazepoxide every 2 to 4 hours until they seem to be out of danger.
Once the delirium appears, however, 50 to 100 mg of chlordiazepoxide should be given
every 4 hours orally, or lorazepam (Ativan) should be given intravenously (IV) if oral
medication is not possible (Table 20.2-5). Antipsychotic medications that may reduce the
seizure threshold in patients should be avoided. A high-calorie, high-carbohydrate diet
supplemented by multivitamins is also important.
Physically restraining patients with the DTs is risky; they may fight against the
restraints to a dangerous level of exhaustion. When patients are disorderly and
uncontrollable, a seclusion room can be used. Dehydration, often exacerbated by
diaphoresis and fever, can be corrected with fluids given by mouth or IV. Anorexia,
vomiting, and diarrhea often occur during withdrawal. Antipsychotic medications should
be avoided because they can reduce the seizure threshold in the patient. The emergence
of focal neurological symptoms, lateralizing seizures, increased intracranial pressure, or
evidence of skull fractures or other indications of CNS pathology should prompt
clinicians to examine a patient for additional neurological disease. Nonbenzodiazepine
anticonvulsant medication is not useful in preventing or treating alcohol withdrawal
convulsions, although benzodiazepines are generally effective.
Warm, supportive psychotherapy in the treatment of DTs is essential. Patients are
often bewildered, frightened, and anxious because of their tumultuous symptoms, and
skillful verbal support is imperative.
Alcohol-Induced Persisting Dementia
Alcohol-induced persisting dementia is a poorly studied, heterogeneous long-term
cognitive problem that can develop in the course of alcoholism. Global decreases in
intellectual functioning, cognitive abilities, and memory are observed, but recent
memory difficulties are consistent with the global cognitive impairment, an observation
that helps to distinguish this from alcohol-induced persisting amnestic disorder. Brain
functioning tends to improve with abstinence, but perhaps half of all affected patients
have long-term and even permanent disabilities in memory and thinking.
Approximately 50 to 70 percent of these patients evidence increased size of the brain
ventricles and shrinkage of the cerebral sulci, although these changes appear to be
partially or completely reversible during the first year of complete abstinence.
Alcohol-Induced Persisting Amnestic Disorder
Diagnosis and Clinical Features.
The essential feature of alcohol-induced
persisting amnestic disorder is a disturbance in short-term memory caused by prolonged
heavy use of alcohol. Because the disorder usually occurs in persons who have been
drinking heavily for many years, the disorder is rare in persons younger than age 35.
Wernicke-Korsakoff Syndrome.
The classic names for alcohol-induced persisting
amnestic disorder are Wernicke’s encephalopathy (a set of acute symptoms) and
Korsakoff’s syndrome (a chronic condition). Whereas Wernicke’s encephalopathy is
completely reversible with treatment, only about 20 percent of patients with Korsakoff’s
syndrome recover. The pathophysiological connection between the two syndromes is
thiamine deficiency, caused either by poor nutritional habits or by malabsorption
problems. Thiamine is a cofactor for several important enzymes and may also be
involved in conduction of the axon potential along the axon and in synaptic
transmission. The neuropathological lesions are symmetrical and paraventricular,
involving the mammillary bodies, the thalamus, the hypothalamus, the midbrain, the
pons, the medulla, the fornix, and the cerebellum.
Wernicke’s encephalopathy, also called alcoholic encephalopathy, is an acute
neurological disorder characterized by ataxia (affecting primarily the gait), vestibular
dysfunction, confusion, and a variety of ocular motility abnormalities, including
horizontal nystagmus, lateral orbital palsy, and gaze palsy. These eye signs are usually
bilateral but not necessarily symmetrical. Other eye signs may include a sluggish
reaction to light and anisocoria. Wernicke’s encephalopathy may clear spontaneously in
a few days or weeks or may progress into Korsakoff’s syndrome.
Treatment.
In the early stages, Wernicke’s encephalopathy responds rapidly to
large doses of parenteral thiamine, which is believed to be effective in preventing the
progression into Korsakoff’s syndrome. The dosage of thiamine is usually initiated at
100 mg by mouth two to three times daily and is continued for 1 to 2 weeks. In patients
with alcohol-related disorders who are receiving IV administration of glucose solution, it
is good practice to include 100 mg of thiamine in each liter of the glucose solution.
Korsakoff’s syndrome is the chronic amnestic syndrome that can follow Wernicke’s
encephalopathy, and the two syndromes are believed to be pathophysiologically related.
The cardinal features of Korsakoff’s syndrome are impaired mental syndrome (especially
recent memory) and anterograde amnesia in an alert and responsive patient. The
patient may or may not have the symptom of confabulation. Treatment of Korsakoff’s
syndrome is also thiamine given 100 mg by mouth two to three times daily; the
treatment regimen should continue for 3 to 12 months. Few patients who progress to
Korsakoff’s syndrome ever fully recover, although many have some improvement in
their cognitive abilities with thiamine and nutritional support.
Blackouts.
Blackouts are similar to episodes of transient global amnesia in that
they are discrete episodes of anterograde amnesia that occur in association with alcohol
intoxication. The periods of amnesia can be particularly distressing when persons fear
that they have unknowingly harmed someone or behaved imprudently while
intoxicated. During a blackout, persons have relatively intact remote memory but
experience a specific short-term memory deficit in which they are unable to recall events
that happened in the previous 5 or 10 minutes. Because their other intellectual faculties
are well preserved, they can perform complicated tasks and appear normal to casual
observers. The neurobiological mechanisms for alcoholic blackouts are now known at
the molecular level; alcohol blocks the consolidation of new memories into old
memories, a process that is thought to involve the hippocampus and related temporal
lobe structures.
Alcohol-Induced Psychotic Disorder
Diagnosis and Clinical Features.
Approximately 3 percent of alcoholic persons
experience auditory hallucinations or paranoid delusions in the context of heavy
drinking or withdrawal. The most common auditory hallucinations are voices, but they
are often unstructured. The voices are characteristically maligning, reproachful, or
threatening, although some patients report that the voices are pleasant and
nondisruptive. The hallucinations usually last less than a week, but during that week
impaired reality testing is common. After the episode, most patients realize the
hallucinatory nature of the symptoms.
Hallucinations after alcohol withdrawal are considered rare, and the syndrome is
distinct from alcohol withdrawal delirium. The hallucinations can occur at any age, but
usually appear in persons abusing alcohol for a long time. Although the hallucinations
usually resolve within a week, some linger; in these cases, clinicians must consider other
psychotic
disorders
in
the
differential
diagnosis.
Alcohol
withdrawal-related
hallucinations are differentiated from the hallucinations of schizophrenia by the
temporal association with alcohol withdrawal, the absence of a classic history of
schizophrenia, and their usually short-lived duration. Alcohol withdrawal-related
hallucinations are differentiated from the DTs by the presence of a clear sensorium in
patients.
Mr. G was a 40-year-old unemployed man living alone in a studio apartment and
was brought to the hospital by the police. He contacted them complaining that he
heard voices of men on the street below his window talking about him and
threatening to kill him. He stated that every time he looked out the window the men
had always disappeared.
Mr. G had a 15-year history of almost daily alcohol use. He was intoxicated each
day and often experienced shakes upon awakening in the morning. On the previous
day, he had only one glass of beer instead of his usual four because of gastrointestinal
problems. He was fully alert and oriented.
Treatment.
The treatment of alcohol withdrawal-related hallucinations is much like
the treatment of DTs—benzodiazepines, adequate nutrition, and fluids, if necessary. If
this regimen fails or for long-term cases, antipsychotics may be used.
Alcohol-Induced Mood Disorder
Heavy intake of alcohol over several days results in many of the symptoms observed in
major depressive disorder, but the intense sadness markedly improves within several
days to 1 month of abstinence. Eighty percent of people with alcoholism report histories
of intense depression, including 30 to 40 percent who were depressed for 2 or more
weeks at a time. However, only 10 to 15 percent of alcoholic persons have ever had
depression that meets the criteria for major depressive disorder when they have not
been drinking heavily.
Even severe substance-induced depressions are likely to improve fairly rapidly with
abstinence, without medication or intensive psychotherapy aimed at the depressive
symptoms. A logical approach for these substance-induced conditions is to teach the
patient how to best view and deal with the temporary sadness through education and
cognitive-behavioral treatment, and to watch and wait at least 2 to 4 weeks before
starting antidepressant medications.
A consultation was requested on a 42-year-old woman with alcohol dependence
who complained of persisting severe depressive symptoms despite 5 days of
abstinence. In the initial stage of the interview, she noted that she had “always been
depressed” and felt that she “drank to cope with the depressive symptoms.” Her
current complaint included a prominent sadness that had persisted for several weeks,
difficulties concentrating, initial and terminal insomnia, and a feeling of hopelessness
and guilt. In an effort to distinguish between an alcohol-induced mood disorder and
an independent major depressive episode, a time-line–based history was obtained.
This focused on the age of onset of alcohol dependence, periods of abstinence that
extended for several months or more since the onset of dependence, and the ages of
occurrence of clear major depressive episodes lasting several weeks or more at a time.
Despite this patient’s original complaints, it became clear that there had been no
major depressive episodes prior to her mid-20s when alcohol dependence began, and
that during a 1-year period of abstinence related to the gestation and neonatal period
of her son, her mood had significantly improved. A provisional diagnosis of an
alcohol-induced mood disorder was made. The patient was offered education,
reassurance, and cognitive therapy to help her to deal with the depressive symptoms,
but no antidepressant medications were prescribed. The depressive symptoms
remained at their original intensity for several additional days and then began to
improve. By approximately 3 weeks abstinent the patient no longer met criteria for a
major depressive episode, although she demonstrated mood swings similar to
dysphemia for several additional weeks. This case is a fairly typical example of an
alcohol-induced mood disorder in an individual with alcohol dependence. (Courtesy of
Marc A. Shuckit, M.D.)
Alcohol-Induced Anxiety Disorder
Anxiety symptoms fulfilling the diagnostic criteria for alcohol-induced anxiety disorder
are also common in the context of acute and protracted alcohol withdrawal. Almost 80
percent of alcoholic persons report panic attacks during at least one acute withdrawal
episode; their complaints can be sufficiently intense for the clinician to consider
diagnosing panic disorder. Similarly, during the first 4 weeks or so of abstinence, people
with severe alcohol problems are likely to avoid some social situations for fear of being
overwhelmed by anxiety (i.e., they have symptoms resembling social phobia); their
problems can at times be severe enough to resemble agoraphobia. However, when
psychological or physiological symptoms of anxiety are observed in alcoholic persons
only in the context of heavy drinking or within the first several weeks or month of
abstinence, the symptoms are likely to diminish and subsequently disappear with time
alone.
A 48-year-old woman was referred for evaluation and treatment of her recent onset
of panic attacks. These episodes occurred two to three times per week over the
preceding 6 months, with each lasting typically between 10 and 20 minutes. Panic
symptoms occurred regardless of levels of life stress and could not be explained by
current medications or medical conditions. The workup included an evaluation of her
laboratory test values, which revealed a carbohydrate-deficient transferrin (CDT) level
of 28 U/L, a uric acid level of 7.1 mg, and a γ-glutamyltransferase value of 47. All
other blood tests were within normal limits.
The atypical age of onset of the panic attacks, along with the blood results,
encouraged the clinician to probe further regarding the pattern of alcohol-related life
problems with both the patient and, separately, her spouse. This step documented a
history of alcohol dependence with an onset at approximately 35 years of age, with
no evidence of panic disorder before that date. Nor did the patient have repetitive
panic attacks beyond 2 weeks of abstinence during her frequent periods of
nondrinking, which often lasted for 3 or 4 months. A working diagnosis of alcohol
dependence with an alcohol-induced anxiety disorder characterized by panic attacks
was made, and the patient was encouraged to abstain and was appropriately treated
for possible withdrawal symptoms. Over the subsequent 3 weeks after a taper of
benzodiazepines used for the treatment of withdrawal, the panic symptoms
diminished in intensity and subsequently disappeared. (Courtesy of Marc A. Schuckit,
M.D.)
Alcohol-Induced Sexual Dysfunction
The formal diagnosis of symptoms of sexual dysfunction associated with alcohol
intoxication is alcohol-induced sexual dysfunction (see Section 17.2).
Alcohol-Induced Sleep Disorder
The diagnostic criteria for alcohol-induced sleep disorders with an onset during either
alcohol intoxication or alcohol withdrawal are found in the sleep disorders section (see
Section 16.2).
Unspecified Alcohol-Related Disorder
The diagnosis of unspecified alcohol-related disorder is used for alcohol-related disorders
that do not meet the diagnostic criteria for any of the other diagnoses.
Idiosyncratic Alcohol Intoxication
Whether there is such a diagnostic entity as idiosyncratic alcohol intoxication is under
debate. Several well-controlled studies of persons who supposedly have the disorder
have raised questions about the validity of the designation. The condition has been
variously called pathologic, complicated, atypical, and paranoid alcohol intoxication; all
these terms indicate that a severe behavioral syndrome develops rapidly after a person
consumes a small amount of alcohol that would have minimal behavioral effects on
most persons. The diagnosis is important in the forensic arena because alcohol
intoxication is not generally accepted as a reason for judging persons not responsible
for their activities. Idiosyncratic alcohol intoxication, however, can be used in a person’s
defense if a defense lawyer can argue successfully that the defendant has an unexpected,
idiosyncratic, pathological reaction to a minimal amount of alcohol.
In anecdotal reports, persons with idiosyncratic alcohol intoxication have been
described as confused and disoriented and as experiencing illusions, transitory delusions,
and visual hallucinations. Persons may display greatly increased psychomotor activity
and impulsive, aggressive behavior. They can be dangerous to others and they may also
exhibit suicidal ideation and make suicide attempts. The disorder, usually described as
lasting for a few hours, terminates in prolonged sleep, and those affected cannot recall
the episodes on awakening. The cause of the condition is unknown, but it is reported to
be most common in persons with high levels of anxiety. According to one hypothesis,
alcohol causes sufficient disorganization and loss of control to release aggressive
impulses. Another suggestion is that brain damage, particularly encephalitic or
traumatic damage, predisposes some persons to an intolerance for alcohol and thus to
abnormal behavior after they ingest only small amounts. Other predisposing factors
may include advancing age, using sedative-hypnotic drugs, and feeling fatigued. A
person’s behavior while intoxicated tends to be atypical; after one weak drink, a quiet,
shy person becomes belligerent and aggressive.
In treating idiosyncratic alcohol intoxication, clinicians must help protect patients
from harming themselves and others. Physical restraint may be necessary, but is difficult
because of the abrupt onset of the condition. Once a patient has been restrained,
injection of an antipsychotic drug, such as haloperidol (Haldol), is useful for controlling
assaultiveness. This condition must be differentiated from other causes of abrupt
behavioral change, such as complex partial epilepsy. Some persons with the disorder
reportedly showed temporal lobe spiking on an EEG after ingesting small amounts of
alcohol.
Other Alcohol-Related Neurological Disorders
Only the major neuropsychiatric syndromes associated with alcohol use have been
discussed here. The complete list of neurological syndromes is lengthy (Table 20.2-6).
Alcoholic pellagra encephalopathy is one diagnosis of potential interest to psychiatrists
presented with a patient who appears to have Wernicke-Korsakoff syndrome but who
does not respond to thiamine treatment. The symptoms of alcoholic pellagra
encephalopathy include confusion, clouding of consciousness, myoclonus, oppositional
hypertonias, fatigue, apathy, irritability, anorexia, insomnia, and sometimes delirium.
Patients have a niacin (nicotinic acid) deficiency, and the specific treatment is 50 mg of
niacin by mouth four times daily or 25 mg parenterally two to three times daily.
Table 20.2-6
Neurological and Medical Complications of Alcohol Use
Fetal Alcohol Syndrome.
Data indicate that women who are pregnant or are
breast-feeding should not drink alcohol. Fetal alcohol syndrome, the leading cause of
intellectual disability in the United States, occurs when mothers who drink alcohol
expose fetuses to alcohol in utero. The alcohol inhibits intrauterine growth and
postnatal development. Microcephaly, craniofacial malformations, and limb and heart
defects are common in affected infants. Short adult stature and development of a range
of adult maladaptive behaviors have also been associated with fetal alcohol syndrome.
Women with alcohol-related disorders have a 35 percent risk of having a child with
defects. Although the precise mechanism of the damage to the fetus is unknown, the
damage seems to result from exposure in utero to ethanol or to its metabolites; alcohol
may also cause hormone imbalances that increase the risk of abnormalities.
PROGNOSIS
Between 10 and 40 percent of alcoholic persons enter some kind of formal treatment
program during the course of their alcohol problems. A number of prognostic signs are
favorable. First is the absence of preexisting antisocial personality disorder or a
diagnosis of other substance abuse or dependence. Second, evidence of general life
stability with a job, continuing close family contacts, and the absence of severe legal
problems also bodes well for the patient. Third, if the patient stays for the full course of
the initial rehabilitation (perhaps 2 to 4 weeks), the chances of maintaining abstinence
are good. The combination of these three attributes predicts at least a 60 percent chance
for 1 or more years of abstinence. Few studies have documented the long-term course,
but researchers agree that 1 year of abstinence is associated with a good chance for
continued abstinence over an extended period. Alcoholic persons with severe drug
problems (especially intravenous drug use or cocaine or amphetamine dependence) and
those who are homeless may have only a 10 to 15 percent chance of achieving 1 year of
abstinence, however.
Accurately predicting whether any specific person will achieve or maintain abstinence
is impossible, but the prognostic factors listed earlier are associated with an increased
likelihood of abstinence. The factors reflecting life stability, however, probably explain
only 20 percent or less of the course of alcohol use disorders. Many forces that are
difficult to measure affect the clinical course significantly; they are likely to include such
intangibles as motivational level and the quality of the patient’s social support system.
In general, alcoholic persons with preexisting independent major psychiatric disorders
—such as antisocial personality disorder, schizophrenia, and bipolar I disorder—are
likely to run the course of their independent psychiatric illness. Thus, for example,
clinicians must treat the patient with bipolar I disorder who has secondary alcoholism
with appropriate psychotherapy and lithium (Eskalith), use relevant psychological and
behavioral techniques for the patient with antisocial personality disorder, and offer
appropriate antipsychotic medications on a long-term basis to the patient with
schizophrenia. The goal is to minimize the symptoms of the independent psychiatric
disorder in the hope that greater life stability will be associated with a better prognosis
for the patient’s alcohol problems.
TREATMENT AND REHABILITATION
Three general steps are involved in treating the alcoholic person after the disorder has
been diagnosed: intervention, detoxification, and rehabilitation. These approaches
assume that all possible efforts have been made to optimize medical functioning and to
address psychiatric emergencies. Thus, for example, an alcoholic person with symptoms
of depression sufficiently severe to be suicidal requires inpatient hospitalization for at
least several days until the suicidal ideation disappears. Similarly, a person presenting
with cardiomyopathy, liver difficulties, or gastrointestinal bleeding first needs adequate
treatment of the medical emergency.
The patient with alcohol abuse or dependence must then be brought face-to-face with
the reality of the disorder (intervention), be detoxified if needed, and begin
rehabilitation. The essentials of these three steps for an alcoholic person with
independent psychiatric syndromes closely resemble the approaches used for the
primary alcoholic person without independent psychiatric syndromes. In the former
case, however, the treatments are applied after the psychiatric disorder has been
stabilized to the extent possible.
Intervention
The goal in the intervention step, which has also been called confrontation, is to break
through feelings of denial and help the patient recognize the adverse consequences
likely to occur if the disorder is not treated. Intervention is a process aimed at
maximizing the motivation for treatment and continued abstinence.
This step often involves convincing patients that they are responsible for their own
actions while reminding them of how alcohol has created significant life impairments.
The psychiatrist often finds it useful to take advantage of the person’s chief presenting
complaint, whether it is insomnia, difficulties with sexual performance, an inability to
cope with life stresses, depression, anxiety, or psychotic symptoms. The psychiatrist can
then explain how alcohol has either created or contributed to these problems and can
reassure the patient that abstinence can be achieved with a minimum of discomfort.
JP, a 47-year-old physician, was confronted regarding his alcohol-related behaviors
by his wife and 21-year-old daughter. They told him about his slurred speech on
several recent occasions when the daughter called home, as well as a large number of
wine bottles in the trash each week. JP’s wife complained of the hours he spent alone
in his study and his practice of staying up after she went to bed, retiring later with
alcohol on his breath. She also related her concern about his consumption of about 10
or 12 drinks at a recent party, with the resulting tendency to isolate himself from the
other guests. She then reminded him of his need to pack liquor when they go on trips
where alcohol may not be readily available, and the tremor of his hands some
mornings after being drunk the night before. The family shared their concern directly
with JP at a time when he was not actively intoxicated, emphasizing specific times
and events when his impairment with alcohol occurred. They had also made an
appointment with the clinician at an alcohol and drug treatment program so that a
next step could be established if the intervention was successful. (Adapted from Marc
A. Schuckit, M.D.)
A physician intervening with a patient can use the same nonjudgmental but persistent
approach each time an alcohol-related impairment is identified. It is the persistence
rather than exceptional interpersonal skills that usually gets results. A single
intervention is rarely sufficient. Most alcoholic persons need a series of reminders of
how alcohol contributed to each developing crisis before they seriously consider
abstinence as a long-term option.
Family
The family can be of great help in the intervention. Family members must learn not to
protect the patient from the problems caused by alcohol; otherwise, the patient may not
be able to gather the energy and the motivation necessary to stop drinking. In addition,
during the intervention stage, the family can suggest that the patient meet with persons
who are recovering from alcoholism, perhaps through AA, and family members can meet
with groups, such as Al-Anon, that reach out to family members. Those support groups
for families meet many times a week and help family members and friends see that they
are not alone in their fears, worry, and feelings of guilt. Participants share coping
strategies and help each other find community resources. The groups can be most useful
in helping family members rebuild their lives, even if the alcoholic person refuses to
seek help.
Detoxification
Most persons with alcohol dependence have relatively mild symptoms when they stop
drinking. If the patient is in relatively good health, is adequately nourished, and has a
good social support system, the depressant withdrawal syndrome usually resembles a
mild case of the flu. Even intense withdrawal syndromes rarely approach the severity of
symptoms described by some early textbooks in the field.
The essential first step in detoxification is a thorough physical examination. In the
absence of a serious medical disorder or combined drug abuse, severe alcohol
withdrawal is unlikely. The second step is to offer rest, adequate nutrition, and multiple
vitamins, especially those containing thiamine.
Mild or Moderate Withdrawal.
Withdrawal develops because the brain has
physically adapted to the presence of a brain depressant and cannot function
adequately in the absence of the drug. Giving sufficient brain depressant on the first day
to diminish symptoms and then weaning the patient off the drug over the next 5 days
offers most patients optimal relief and minimizes the possibility that severe withdrawal
will develop. Any depressant—including alcohol, barbiturates, or any of the
benzodiazepines—can work, but most clinicians choose a benzodiazepine for its relative
safety. Adequate treatment can be given with either short-acting drugs (e.g.,
lorazepam), or long-acting substances (e.g., chlordiazepoxide and diazepam).
An example of treatment is the administration of 25 mg of chlordiazepoxide by mouth three or four times a day on the
first day, with a notation to skip a dose if the patient is asleep or feeling sleepy. An additional one or two 25-mg doses can
be given during the first 24 hours if the patient is jittery or shows signs of increasing tremor or autonomic dysfunction.
Whatever benzodiazepine dosage is required on the first day can be decreased by 20 percent each subsequent day, with a
resulting need for no further medication after 4 or 5 days. When giving a long-acting agent, such as chlordiazepoxide, the
clinician must avoid producing excessive sleepiness through overmedication; if the patient is sleepy, the next scheduled
dose should be omitted. When taking a short-acting drug, such as lorazepam, the patient must not miss any dose because
rapid changes in benzodiazepine concentrations in the blood can precipitate severe withdrawal.
A social model program of detoxification saves money by avoiding medications while using social supports. This lessexpensive regimen can be helpful for mild or moderate withdrawal syndromes. Some clinicians have also recommended βadrenergic receptor antagonists (e.g., propranolol [Inderal]) or α-adrenergic receptor agonists (e.g., clonidine), although
these medications do not appear to be superior to the benzodiazepines. Unlike the brain depressants, these other agents do
little to decrease the risk of seizures or delirium.
Severe Withdrawal.
For the approximately 1 percent of alcoholic patients with
extreme autonomic dysfunction, agitation, and confusion—that is, those with alcoholic
withdrawal delirium, or DTs—no optimal treatment has yet been developed. The first
step is to ask why such a severe and relatively uncommon withdrawal syndrome has
occurred; the answer often relates to a severe concomitant medical problem that needs
immediate treatment. The withdrawal symptoms can then be minimized through the use
of either benzodiazepines (in which case high doses are sometimes required) or
antipsychotic agents, such as haloperidol. Once again, on the first or second day, doses
are used to control behavior, and the patient can be weaned off the medication by about
the fifth day.
Another 1 percent of patients may have a single grand mal convulsion; the rare person has multiple fits, with the peak
incidence on the second day of withdrawal. Such patients require neurological evaluation, but in the absence of evidence
of a seizure disorder, they do not benefit from anticonvulsant drugs.
Protracted Withdrawal.
Symptoms of anxiety, insomnia, and mild autonomic
overactivity are likely to continue for 2 to 6 months after the acute withdrawal has
disappeared. Although no pharmacological treatment for this syndrome appears
appropriate, it is possible that some of the medications used for the rehabilitation phase,
especially acamprosate (Campral), may work by diminishing some of these symptoms.
It is important that the clinician warn the patient that some level of sleep problems or
feelings of nervousness might remain after acute withdrawal and discuss cognitive and
behavioral approaches that might be appropriate to helping the patient feel more
comfortable. These protracted withdrawal symptoms may enhance the probability of
relapse.
Rehabilitation
For most patients, rehabilitation includes three major components: (1) continued efforts
to increase and maintain high levels of motivation for abstinence; (2) work to help the
patient readjust to a lifestyle free of alcohol; and (3) relapse prevention. Because these
steps are carried out in the context of acute and protracted withdrawal syndromes and
life crises, treatment requires repeated presentations of similar materials that remind
the patient how important abstinence is and that help the patient develop new day-today support systems and coping styles.
No single major life event, traumatic life period, or identifiable psychiatric disorder is
known to be a unique cause of alcoholism. In addition, the effects of any causes of
alcoholism are likely to have been diluted by the effects of alcohol on the brain and the
years of an altered lifestyle, so that the alcoholism has developed a life of its own. This
is true even though many alcoholic persons believe that the cause was depression,
anxiety, life stress, or pain syndromes. Research, data from records, and resource
persons usually reveal that alcohol contributed to the mood disorder, accident, or life
stress, not vice versa.
The same general treatment approach is used in inpatient and outpatient settings.
Selection of the more expensive and intensive inpatient mode often depends on
evidence of additional severe medical or psychiatric syndromes, the absence of
appropriate nearby outpatient groups and facilities, and the patient’s history of having
failed in outpatient care. The treatment process in either setting involves intervention,
optimizing physical and psychological functioning, enhancing motivation, reaching out
to family, and using the first 2 to 4 weeks of care as an intensive period of help. Those
efforts must be followed by at least 3 to 6 months of less frequent outpatient care.
Outpatient care uses a combination of individual and group counseling, judicious
avoidance of psychotropic medications unless needed for independent disorders, and
involvement in such self-help groups as AA.
Counseling.
Counseling efforts in the first several months should focus on day-today life issues to help patients maintain a high level of motivation for abstinence and to
enhance their functioning. Psychotherapy techniques that provoke anxiety or that
require deep insights have not been shown to be of benefit during the early months of
recovery and, at least theoretically, may actually impair efforts at maintaining
abstinence. Thus, this discussion focuses on the efforts likely to characterize the first 3 to
6 months of care.
Counseling or therapy can be carried out in an individual or group setting; few data
indicate that either approach is superior. The technique used is not likely to matter
greatly and usually boils down to simple day-to-day counseling or almost any
behavioral or psychotherapeutic approach focusing on the here and now. To optimize
motivation, treatment sessions should explore the consequences of drinking, the likely
future course of alcohol-related life problems, and the marked improvement that can be
expected with abstinence. Whether in an inpatient or an outpatient setting, individual
or group counseling is usually offered a minimum of three times a week for the first 2 to
4 weeks, followed by less intense efforts, perhaps once a week, for the subsequent 3 to 6
months.
Much time in counseling deals with how to build a lifestyle free of alcohol. Discussions
cover the need for a sober peer group, a plan for social and recreational events without
drinking, and approaches for reestablishing communication with family members and
friends.
The third major component, relapse prevention, first identifies situations in which the
risk for relapse is high. The counselor must help the patient develop modes of coping to
be used when the craving for alcohol increases or when any event or emotional state
makes a return to drinking likely. An important part of relapse prevention is reminding
the patient about the appropriate attitude toward slips. Short-term experiences with
alcohol can never be used as an excuse for returning to regular drinking. The efforts to
achieve and maintain a sober lifestyle are not a game in which all benefits are lost with
that first sip. Rather, recovery is a process of trial and error; patients use slips that occur
to identify high-risk situations and to develop more appropriate coping techniques.
Most treatment efforts recognize the effects that alcoholism has on the significant
persons in the patient’s life, and an important aspect of recovery involves helping
family members and close friends understand alcoholism and realize that rehabilitation
is an ongoing process that lasts for 6 to 12 or more months. Couples and family
counseling and support groups for relatives and friends help the persons involved to
rebuild relationships, to learn how to avoid protecting the patient from the
consequences of any drinking in the future, and to be as supportive as possible of the
alcoholic patient’s recovery program.
Medications.
If detoxification has been completed and the patient is not one of the
10 to 15 percent of alcoholic persons who have an independent mood disorder,
schizophrenia, or anxiety disorder, little evidence favors prescribing psychotropic
medications for the treatment of alcoholism. Lingering levels of anxiety and insomnia as
part of a reaction to life stresses and protracted abstinence should be treated with
behavior modification approaches and reassurance. Medications for these symptoms
(including benzodiazepines) are likely to lose their effectiveness much faster than the
insomnia disappears; thus, the patient may increase the dose and have subsequent
problems. Similarly, sadness and mood swings can linger at low levels for several
months. Controlled clinical trials, however, indicate no benefit in prescribing
antidepressant medications or lithium to treat the average alcoholic person who has no
independent or long-lasting psychiatric disorder. The mood disorder will clear before the
medications can take effect, and patients who resume drinking while on the medications
face significant potential dangers. With little or no evidence that the medications are
effective, the dangers significantly outweigh any potential benefits from their routine
use.
One possible exception to the proscription against the use of medications is the
alcohol-sensitizing agent disulfiram. Disulfiram is given in daily doses of 250 mg before
the patient is discharged from the intensive first phase of outpatient rehabilitation or
from inpatient care. The goal is to place the patient in a condition in which drinking
alcohol precipitates an uncomfortable physical reaction, including nausea, vomiting,
and a burning sensation in the face and stomach. Few data prove that disulfiram is
more effective than a placebo, however, probably because most persons stop taking the
disulfiram when they resume drinking. Many clinicians have stopped routinely
prescribing the agent, partly in recognition of the dangers associated with the drug
itself: mood swings, rare instances of psychosis, the possibility of increased peripheral
neuropathies, the relatively rare occurrence of other significant neuropathies, and
potentially fatal hepatitis. Moreover, patients with preexisting heart disease, cerebral
thrombosis, diabetes, and a number of other conditions cannot be given disulfiram
because an alcohol reaction to the disulfiram could be fatal.
Two additional promising pharmacological interventions have recently been studied.
The first involves the opioid antagonist naltrexone (ReVia), which at least theoretically
is believed possibly to decrease the craving for alcohol or blunt the rewarding effects of
drinking. In any event, two relatively small (approximately 90 patients on the active
drug across the studies) and short-term (3 months of active treatment) investigations
using 50 mg per day of this drug had potentially promising results. Evaluating the full
impact of this medication, however, will require longer-term studies of relatively large
groups of more diverse patients.
The second medication of interest, acamprosate (Campral), has been tested in more
than 5,000 alcohol-dependent patients in Europe. This drug is not yet available in the
United States. Used in dosages of approximately 2,000 mg per day, this medication was
associated with approximately 10 to 20 percent more positive outcomes than placebo
when used in the context of the usual psychological and behavioral treatment regimens
for alcoholism. The mechanism of action of acamprosate is not known, but it may act
directly or indirectly at GABA receptors or at NMDA sites, the effects of which alter the
development of tolerance or physical dependence on alcohol. A summary of medications
used for alcohol dependence is given in Table 20.2-7.
Table 20.2-7
Medications for Treating Alcohol Dependence
Another medication with potential promise in the treatment of alcoholism is the
nonbenzodiazepine antianxiety drug buspirone (BuSpar), although the effect of this drug
on alcohol rehabilitation is inconsistent between studies. No evidence exists that
antidepressant medications, such as the selective serotonin reuptake inhibitors (SSRIs),
lithium, or antipsychotic medications, are significantly effective in the treatment of
alcoholism.
Alcoholics Anonymous.
Clinicians must recognize the potential importance of
self-help groups such as AA. Members of AA have help available 24 hours a day,
associate with a sober peer group, learn that it is possible to participate in social
functions without drinking, and are given a model of recovery by observing the
accomplishments of sober members of the group.
Learning about AA usually begins during inpatient or outpatient rehabilitation. The
clinician can play a major role in helping patients understand the differences between
specific groups. Some are composed only of men or women, and others are mixed; some
meetings are composed mostly of blue collar men and women, whereas others are
mostly for professionals; some groups place great emphasis on religion, and others are
eclectic. Patients with coexisting psychiatric disorders may need some additional
education about AA. The clinician should remind them that some members of AA may
not understand their special need for medications and should arm the patients with
ways of coping when group members inappropriately suggest that the required
medications be stopped. Although difficult to evaluate using double-blind controls, most
studies indicate that participation in AA is associated with improved outcomes, and
incorporation into treatment programs saves money.
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2013;13:199.
Choo ED, McGregor AJ, Mello MJ, Baird J. Gender, violence and brief interventions for alcohol in the emergency
department. Drug Alcohol Depend. 2013;127:115.
Incerti M, Vink J, Roberson R, Benassou I, Abebe D, Spong CY. Prevention of the alcohol-induced changes in brain-derived
neurotrophic factor expression using neuroprotective peptides in a model of fetal alcohol syndrome. Am J Obstet
Gynecol. 2010;202(5):457.
Jackson KM, Bucholz KK, Wood PK, Steinley D, Grant JD, Sher KJ. Towards the characterization and validation of alcohol
use disorder subtypes: integrating consumption and symptom data. Psychol Med . 2014;44(01):143–159.
Johnson BA. Medication treatment of different types of alcoholism. Am J Psychiatry. 2010; 167:630.
Johnson BA, Marzani-Nissen G. Alcohol. Clinical Aspects. In: Johnson BA, ed. Addiction Medicine: Science and Practice.
New York: Springer; 2011:381.
MacKillop J, Miranda R, Jr., Monti PM, Ray LA, Murphy JG, Rohsenow DJ, McGeary JE, Swift RM, Tidey JW, Gwaltney
CJ. Alcohol demand, delayed reward discounting, and craving in relation to drinking and alcohol use disorders. J Abnorm
Psychol. 2010;11:106.
Moberg CA, Curtin JJ. Alcohol selectively reduces anxiety but not fear: startle response during unpredictable versus
predictable threat. J Abnorm Psychol. 2009;118(2):335.
Morgan T, White H, Mun E. Changes in drinking before a mandated brief intervention with college students. J Stud Alcohol
Drugs. 2008;69:286.
Nilsen P. Brief alcohol intervention—where to from here? Challenges remain for research and practice. Addiction.
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Oreskovich MR, Kaups KL, Balch CM, Hanks JB, Satele D, Sloan J, Meredith C, Buhl A, Dyrbye LN, Shanafelt TD.
Prevalence of alcohol use disorders among American surgeons. JAMA Arch Surg. 2012;147(2):168.
Rasmussen C, Bisnaz J. Executive functioning in children with Fetal Alcohol Spectrum Disorders: Profiles and age-related
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Schuckit MA. Alcohol-related disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook

03 - 20.3 Caffeine Related Disorders
20.3 Caffeine-Related Disorders
of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:1268.
Vergés A, Jackson KM, Bucholz KK, Grant JD, Trull TJ, Wood PK, Sher KJ. Deconstructing the age-prevalence curve of
alcohol dependence: Why “maturing out” is only a small piece of the puzzle. J Abnormal Psychol. 2012;121:511.
20.3 Caffeine-Related Disorders
Caffeine is the most widely consumed psychoactive substance in the world. Caffeine is
found in more than 60 species of plants and belongs to the methylxanthine class of
alkaloids, which also includes theobromine (found in chocolate) and theophylline (often
used in the treatment of asthma). In the United States, 87 percent of children and adults
consume
foods
and
beverages
containing
caffeine.
Caffeine
affects
various
neurobiological and physiological systems and produces significant psychological
effects. Caffeine is not associated with any life-threatening illnesses, but its use can
result in psychiatric symptoms and disorders. The habitual use of caffeine and its widely
accepted integration into daily customs can lead to an underestimation of the role that
caffeine may play in one’s daily life and can make the recognition of caffeine-associated
disorders particularly challenging. Hence, it is important for the clinician to be familiar
with caffeine, its effects, and problems that can be associated with its use.
Caffeine use is associated with five disorders: caffeine use disorder, caffeine
intoxication, caffeine withdrawal, caffeine-induced anxiety disorder, and caffeineinduced sleep disorder.
EPIDEMIOLOGY
Caffeine is contained in drinks, foods, prescription medicines, and over-the-counter
medicines (Table 20.3-1). An adult in the United States consumes about 200 mg of
caffeine per day on average, although 20 to 30 percent of all adults consume more than
500 mg per day. The per capita use of coffee in the United States is 10.2 pounds per
year. A cup of coffee generally contains 100 to 150 mg of caffeine; tea contains about
one third as much. Many over-the-counter medications contain one third to one half as
much caffeine as a cup of coffee, and some migraine medications and over-the-counter
stimulants contain more caffeine than a cup of coffee. Cocoa, chocolate, and soft drinks
contain significant amounts of caffeine, enough to cause some symptoms of caffeine
intoxication in small children when they ingest a candy bar and a 12-ounce cola drink.
Table 20.3-1
Common Sources of Caffeine and Representative Decaffeinated Products
Caffeine consumption also varies by age. The average daily caffeine consumption of
caffeine consumers of all ages is 2.79 mg/kg of body weight in the United States. A
substantial amount of caffeine is consumed even by young children (i.e., more than 1
mg/kg for children between the ages of 1 and 5 years). Worldwide, estimates place the
average daily per capita caffeine consumption at about 70 mg. Up to 85 percent of
adults consume caffeine in any given year.
COMORBIDITY
Persons with caffeine-related disorders are more likely to have additional substancerelated disorders than are those without diagnoses of caffeine-related disorders. About
two thirds of those who consume large amounts of caffeine daily also use sedative and
hypnotic drugs.
ETIOLOGY
After exposure to caffeine, continued caffeine consumption can be influenced by several
different factors, such as the pharmacological effects of caffeine, caffeine’s reinforcing
effects, genetic predispositions to caffeine use, and personal attributes of the consumer.
Neuropharmacology
Caffeine, a methylxanthine, is more potent than another commonly used methylxanthine, theophylline (Primatene). The
half-life of caffeine in the human body is 3 to 10 hours, and the time of peak concentration is 30 to 60 minutes. Caffeine
readily crosses the blood–brain barrier. Caffeine acts primarily as an antagonist of the adenosine receptors. Adenosine
receptors activate an inhibitory G protein (Gi) and, thus, inhibit the formation of the second-messenger cyclic adenosine
monophosphate (cAMP). Caffeine intake, therefore, results in an increase in intraneuronal cAMP concentrations in neurons
with adenosine receptors. Three cups of coffee are estimated to deliver so much caffeine to the brain that about 50 percent
of the adenosine receptors are occupied by caffeine. Several experiments indicate that caffeine, especially at high doses or
concentrations, can affect dopamine and noradrenergic neurons. Specifically, dopamine activity may be enhanced by
caffeine, a hypothesis that could explain clinical reports associating caffeine intake with an exacerbation of psychotic
symptoms in patients with schizophrenia. Activation of noradrenergic neurons has been hypothesized to be involved in
the mediation of some symptoms of caffeine withdrawal.
Subjective Effects and Reinforcement
Single low to moderate doses of caffeine (i.e., 20 to 200 mg) can produce a profile of subjective effects in humans that is
generally identified as pleasurable. Thus, studies have shown that such doses of caffeine result in increased ratings on
measures such as well-being, energy and concentration, and motivation to work. In addition, these doses of caffeine
produce decreases in ratings of feeling sleepy or tired. Doses of caffeine in the range of 300 to 800 mg (the equivalent of
several cups of brewed coffee ingested at once) produce effects that are often rated as being unpleasant, such as anxiety and
nervousness. Although animal studies have generally found it difficult to demonstrate that caffeine functions as a
reinforcer, well-controlled studies in humans have shown that people choose caffeine over placebo when given the choice
under controlled experimental conditions. In habitual users, the reinforcing effects of caffeine are potentiated by the ability
to suppress low-grade withdrawal symptoms after overnight abstinence. Thus, the profile of caffeine’s subjective effects
and its ability to function as a reinforcer contribute to the regular use of caffeine.
Genetics and Caffeine Use
Some genetic predisposition may exist to continued coffee use after exposure to coffee. Investigations comparing coffee or
caffeine use in monozygotic and dizygotic twins have shown higher concordance rates for monozygotic twins for total
caffeine consumption, heavy use, caffeine tolerance, caffeine withdrawal, and caffeine intoxication, with heritabilities
ranging between 35 and 77 percent. Multivariate structural equation modeling of caffeine use, cigarette smoking, and
alcohol use suggests that a common genetic factor—polysubstance use—underlies use of these three substances.
Age, Sex, and Race
The relationship between long-term chronic caffeine use and demographical features, such as age, sex, and race, has not
been widely studied. Some evidence suggests that middle-aged people may use more caffeine, although caffeine use in
adolescents is not uncommon. No known evidence indicates that caffeine use differs between men and women, and no data
specifically address caffeine use for different races. Some evidence suggests that, for both children and adults in the United
States, whites consume more caffeine than blacks.
Special Populations
Cigarette smokers consume more caffeine than nonsmokers. This observation may reflect a common genetic vulnerability
to caffeine use and cigarette smoking. It may also be related to increased rates of caffeine elimination in cigarette smokers.
Preclinical and clinical studies indicate that regular caffeine use can potentiate the reinforcing effects of nicotine.
Heavy use and clinical dependence on alcohol is associated with heavy use and clinical dependence on caffeine as well.
Individuals with anxiety disorders tend to report lower levels of caffeine use, although one study showed that a greater
proportion of heavy caffeine consumers also use benzodiazepines. Several studies have also shown high daily amounts of
caffeine use in psychiatric in-patients. For example, several studies have found that such patients consume the equivalent
of an average of five or more cups of brewed coffee each day. Finally, high daily caffeine consumption has also been noted
in prisoners.
Personality
Although attempts have been made to link preferential use of caffeine to particular personality types, results from these
studies do not suggest that any particular personality type is especially linked to caffeine use.
Effects on Cerebral Blood Flow
Most studies have found that caffeine results in global cerebral vasoconstriction, with a
resultant decrease in cerebral blood flow (CBF), although this effect may not occur in
persons over 65 years of age. According to one recent study, tolerance does not develop
to these vasoconstrictive effects, and the CBF shows a rebound increase after withdrawal
from caffeine. Some clinicians believe that caffeine use can cause a similar constriction
in the coronary arteries and produce angina in the absence of atherosclerosis.
DIAGNOSIS
The diagnosis of caffeine intoxication or other caffeine-related disorders depends
primarily on a comprehensive history of a patient’s intake of caffeine-containing
products. The history should cover whether a patient has experienced any symptoms of
caffeine withdrawal during periods when caffeine consumption was either stopped or
severely reduced. The differential diagnosis for caffeine-related disorders should include
the following psychiatric diagnoses: generalized anxiety disorder, panic disorder with or
without agoraphobia, bipolar II disorder, attention-deficit/hyperactivity disorder
(ADHD), and sleep disorders. The differential diagnosis should include the abuse of
caffeine-containing
over-the-counter
medications,
anabolic
steroids,
and
other
stimulants, such as amphetamines and cocaine. A urine sample may be needed to screen
for these substances. The differential diagnosis should also include hyperthyroidism and
pheochromocytoma.
Caffeine Intoxication
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)
diagnostic criteria for caffeine intoxication includes the recent consumption of caffeine,
usually in excess of 250 mg. The annual incidence of caffeine intoxication is an
estimated 10 percent, although some clinicians and investigators suspect that the actual
incidence is much higher. The common symptoms associated with caffeine intoxication
include
anxiety,
psychomotor
agitation,
restlessness,
irritability,
and
psychophysiological complaints such as muscle twitching, flushed face, nausea, diuresis,
gastrointestinal distress, excessive perspiration, tingling in the fingers and toes, and
insomnia. Consumption of more than 1 g of caffeine can produce rambling speech,
confused thinking, cardiac arrhythmias, inexhaustibleness, marked agitation, tinnitus,
and mild visual hallucinations (light flashes). Consumption of more than 10 g of
caffeine can cause generalized tonic–clonic seizures, respiratory failure, and death.
Ms. B, a 30-year-old, went for consultation due to “anxiety attacks.” The attacks
occurred mid- to late afternoon, when Ms. B became restless, nervous, and easily
excited and sometimes was noticed to be flushed, sweating, and, according to
coworkers, “talking a mile a minute.” In response to questioning, Ms. B admitted to
consuming six to seven cups of coffee each day before the time the attacks usually
occurred.
Caffeine Withdrawal
The appearance of withdrawal symptoms reflects the tolerance and physiological
dependence that develop with continued caffeine use. Several epidemiological studies
have reported symptoms of caffeine withdrawal in 50 to 75 percent of all caffeine users
studied. The most common symptoms are headache and fatigue; other symptoms include
anxiety, irritability, mild depressive symptoms, impaired psychomotor performance,
nausea, vomiting, craving for caffeine, and muscle pain and stiffness. The number and
severity of the withdrawal symptoms are correlated with the amount of caffeine
ingested and the abruptness of the withdrawal. Caffeine withdrawal symptoms have
their onset 12 to 24 hours after the last dose; the symptoms peak in 24 to 48 hours and
resolve within 1 week.
The induction of caffeine withdrawal can sometimes be iatrogenic. Physicians often
ask their patients to discontinue caffeine intake before certain medical procedures, such
as endoscopy, colonoscopy, and cardiac catheterization. In addition, physicians often
recommend that patients with anxiety symptoms, cardiac arrhythmias, esophagitis,
hiatal hernias, fibrocystic disease of the breast, and insomnia stop caffeine intake. Some
persons simply decide that it would be good for them to stop using caffeine-containing
products. In all these situations, caffeine users should taper the use of caffeinecontaining products over a 7- to 14-day period rather than stop abruptly.
Mr. F was a 43-year-old attorney who was brought for a psychiatric consultation by
his wife. Mr. F had been complaining of fatigue, loss of motivation, sleepiness,
headache, nausea, and difficulty concentrating. His symptoms occurred mostly over
the weekends. He withdrew from weekend social activities due to his symptoms,
which worried Mrs. F because he seems fine during the week. Mr. F is in good health
with no recent history of medical disorders.
Mr. F worked in a very busy law practice, many times working 60-hour weeks, and
barely sees his family during the week. At work he is often anxious, restless, and
constantly busy. He worries about his job so much that he has difficulty sleeping on
weeknights. He denies any marital or family problems, other than those caused by his
not wanting to do anything over the weekend.
At work, Mr. F regularly consumes approximately 4 to 5 cups of coffee per day. He
cut out coffee on the weekends because he felt that it may be contributing to his
anxiety and sleeplessness.
Caffeine-Induced Anxiety Disorder
The anxiety related to caffeine use can resemble that of generalized anxiety disorder.
Patients with the disorder may be perceived as “wired,” overly talkative, and irritable;
they may complain of not sleeping well and of having energy to burn. Caffeine can
induce and exacerbate panic attacks in persons with a panic disorder, and although a
causative association between caffeine and a panic disorder has not yet been
demonstrated, patients with panic disorder should avoid caffeine.
Mr. B was a 28-year-old single African American male graduate student who was in
good health and had no history of previous psychiatric evaluation or treatment. He
took no medications, did not smoke or consume alcohol, and had no current or past
history of illicit drug use.
His chief complaint was that he had begun feeling mounting “anxiety” when
working in the laboratory where he was pursuing his graduate studies. His work had
been progressive well, he felt his relationship with his advisor was good and
supportive, and he could not identify any problems with staff or peers that might
explain his anxiety. He had been working long hours, but found the work interesting
and had recently had his first paper accepted for publication.
Despite these successes, he reported feeling a “crescendoing anxiety” as his day
would progress. He noted that by the afternoon he would be experiencing
palpitations, bursts of his heart racing, tremors in his hands, and an overall feeling of
“being on the edge.” He also noted a nervous energy in the afternoons. These
experiences were occurring daily and seemed confined to the laboratory (although he
admitted he was in the laboratory every day of the week).
When reviewing Mr. B’s caffeine intake, it was found that he was consuming
excessive amounts of coffee. Staff made a large urn of caffeinated coffee each
morning, and Mr. B routinely started with a large mug of coffee. Over the course of
the morning he would consume three to four mugs of coffee (the equivalent of about
six or eight 6-oz cups of coffee), and continued this level of use throughout the
afternoon. He occasionally had a single can of a caffeinated soft drink, and used no
other forms of caffeine on a regular basis. Mr. B estimated that he drank a total of six
to eight or more mugs of coffee per day (which was estimated to be at least 1,200 mg
of caffeine per day). Once pointed out to him, he realized that this level of caffeine
consumption was considerably higher than at any other time in his life. He admitted
he liked the taste of coffee and felt a burst of energy in the morning when he drank
coffee that helped him start his day.
Mr. B and his physician developed a plan to decrease his caffeine use by tapering
off caffeine. Mr. B was successful in decreasing his caffeine use and had good
resolution of his anxiety symptoms once his daily caffeine use had markedly
decreased. (Courtesy of Laura M. Juliano, Ph.D., and Roland R. Griffiths, Ph.D.)
Caffeine-Induced Sleep Disorder
Caffeine is associated with delay in falling asleep, inability to remain asleep, and early
morning awakening.
Caffeine Use Disorder
A diagnosis of caffeine use disorder can be given in some people with problematic
caffeine consumption. It is included in Section III of DSM-5, which is reserved for
conditions that require further research. No studies have examined the course and
prognosis for patients with a diagnosis of caffeine use disorder. Subjects with caffeine
use disorder have reported continued use of caffeine despite repeated efforts to
discontinue their caffeine use.
Ms. G was a 35-year-old married, white homemaker with three children, aged 8, 6,
and 2. She took no prescription medications, took a multivitamin and vitamins C and
E on a daily basis, did not smoke, and had no history of psychiatric problems. She
drank moderate amounts of alcohol on the weekends, had smoked marijuana in
college but had not used it since, and had no other history of illicit drug use.
She had started consuming caffeinated beverages while in college, and her current
beverage of choice was caffeinated diet cola. Ms. G had her first soft drink early in the
morning, shortly after getting out of bed, and she jokingly called it her “morning hit.”
She spaced out her bottles of soft drinks over the course of the day, with her last bottle
at dinnertime. She typically drank four to five 20-oz bottles of caffeinated diet cola
each day.
She and her husband had argued about her caffeinated soft drink use in the past,
and her husband had believed she should not drink caffeinated soft drinks while
pregnant. However, she had continued to do so during each of her pregnancies.
Despite a desire to stop drinking caffeinated soft drinks, she was unable to do so. She
described having a strong desire to drink caffeinated soft drinks, and if she resisted
this desire, she found that she could not think of anything else. She drank caffeinated
soft drinks in her car, which had a manual transmission, and noted that she fumbled
while shifting and holding the soft drink and spilled it in the car. She also noted that
her teeth had become yellowed, and she suspected this was related to her tendency to
swish soft drink in her mouth before swallowing it. When asked to describe a time
when she stopped using soft drinks, she reported that she had run out of it on the day
one of her children was to have a birthday party, and she did not have time to leave
her home to buy more. In the early afternoon of that day, a few hours before the
scheduled start of the party, she felt extreme lethargy, a severe headache, irritability,
and craving for a soft drink. She called her husband and told him she planned to
cancel the party. She then went to the grocery store to buy soft drinks, and after
drinking two bottles, she felt well enough to host the party.
Although initially expressing interest in decreasing or stopping her caffeinated soft
drink use, Ms. G did not attend scheduled follow-up appointments after her first
evaluation. When finally contacted at home, she reported she had only sought help
initially at her husband’s request, and she had decided to try to cut down on her
caffeine use on her own. (Courtesy of Eric Stain, M.D.)
Caffeine-Related Disorder Not Elsewhere Classified
This category is used for caffeine-related disorders that do not meet the criteria for
caffeine use disorder, caffeine intoxication, caffeine withdrawal, caffeine-induced
anxiety disorder, or caffeine-induced sleep disorder.
CLINICAL FEATURES
Signs and Symptoms
After the ingestion of 50 to 100 mg of caffeine, common symptoms include increased
alertness, a mild sense of well-being, and a sense of improved verbal and motor
performance. Caffeine ingestion is also associated with diuresis, cardiac muscle
stimulation, increased intestinal peristalsis, increased gastric acid secretion, and (usually
mildly) increased blood pressure.
Caffeine Use and Nonpsychiatric Illnesses
Despite numerous studies examining the relationship between caffeine use and physical
illness, significant health risk from nonreversible pathological consequences of caffeine
use, such as cancer, heart disease, and human reproduction, has not been conclusively
demonstrated. Nonetheless, caffeine use is often considered to be contraindicated for
various conditions, including generalized anxiety disorder, panic disorder, primary
insomnia, gastroesophageal reflux, and pregnancy. In addition, the modest ability of
caffeine to increase blood pressure and the documented cholesterol-elevating compounds
of unfiltered coffee have raised the issue of the relationship of caffeine and coffee use to
cardiovascular disease. Finally, there may be a mild association between higher daily
caffeine use in women and delayed conception and slightly lower birth weight. Studies,
however, have not found such associations, and effects, when found, are usually with
relatively high daily dosages of caffeine (e.g., the equivalent of five cups of brewed
coffee per day). For a woman who is considering pregnancy, especially if there is some
difficulty in conceiving, it may be useful to counsel the elimination of caffeine use.
Similarly, for a woman who becomes pregnant and has moderate to high daily caffeine
consumption, a discussion about decreasing her daily caffeine use may be warranted.
TREATMENT
Analgesics, such as aspirin, almost always can control the headaches and muscle aches
that may accompany caffeine withdrawal. Rarely do patients require benzodiazepines to
relieve withdrawal symptoms. If benzodiazepines are used for this purpose, they should
be used in small dosages for a brief time, about 7 to 10 days at the longest.
The first step in reducing or eliminating caffeine use is to have patients determine
their daily consumption of caffeine. This can best be accomplished by having the patient
keep a daily food diary. The patient must recognize all sources of caffeine in the diet,
including forms of caffeine (e.g., beverages, medications), and accurately record the
amount consumed. After several days of keeping such a diary, the clinician can meet
with the patient, review the diary, and determine the average daily caffeine dose in
milligrams.
The patient and clinician should then decide on a fading schedule for caffeine
consumption. Such a schedule could involve a decrease in increments of 10 percent
every few days. Because caffeine is typically consumed in beverage form, the patient
can use a substitution procedure in which a decaffeinated beverage is gradually used in
place of the caffeinated beverage. The diary should be maintained during this time, so
that the patient’s progress can be monitored. The fading should be individualized for
each patient, so that the rate of decrease in caffeine consumption minimizes withdrawal
symptoms. The patient should probably avoid stopping all caffeine use abruptly,
because withdrawal symptoms are likely to develop with sudden discontinuation of all
caffeine use.
REFERENCES
Bhorkar AA, Dandekar MP, Nakhate KT, Subhedar NK, Kokare DM. Involvement of the central melanocortin system in the
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Butt MS, Sultan MT. Coffee and its consumption: Benefits and risks. Crit Rev Food Sci Nutr. 2011;51:363.
Jonjev ZS, Bala G. High-energy drinks may provoke aortic dissection. Coll Antropol. 2013;37:227.
Juliano LM, Griffiths RR. Caffeine-related disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s
Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:1296.
Kennedy DO, Haskell CF. Cerebral blood flow and behavioural effects of caffeine in habitual and non-habitual consumers of

04 - 20.4 Cannabis Related Disorders
20.4 Cannabis-Related Disorders
caffeine: A near infrared spectroscopy study. Biol Psychol. 2011;86:298.
Lieberman JA III, Sylvester L, Paik S. Excessive sleepiness and self-reported shift work disorder: an Internet survey of shift
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Ludden AB, Wolfson AR. Understanding adolescent caffeine use: Connecting use patterns with expectancies, reasons, and
sleep. Health Educ Behav. 2010;37:330.
Mahoney CR, Brunyé TT, Giles GE. Caffeine effects on aggression and risky decision making. In: Kanarek RB, Lieberman
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Reissig CJ, Strain EC, Griffiths RR. Caffeinated energy drinks—A growing problem. Drug Alcohol Depend. 2009;99:1.
Sepkowitz KA. Energy drinks and caffeine-related adverse effects. JAMA. 2013;309:243.
Stafford LD, Wright C, Yeomans MR. The drink remains the same: Implicit positive associations in high but not moderate
or non-caffeine users. Psychology Addict Behav. 2010;24:274.
Yang A, Palmer AA, de Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology.
2010;211:245.
20.4 Cannabis-Related Disorders
Cannabis is the most widely used illegal drug in the world, with an estimate 19 million
users in 2012. Over the last 30 years cannabis has become a common part of youth
culture in most developed societies, with first use now occurring in the mid- to late
teenage years. Cannabis is the fourth most commonly used psychoactive drug among
adults in the United States, after caffeine, alcohol, and nicotine.
CANNABIS PREPARATIONS
Cannabis preparations are obtained from the plant Cannabis sativa (Fig. 20.4-1), which
has been used in China, India, and the Middle East for approximately 8,000 years,
primarily for its fibers and secondarily for its medicinal properties. The plant occurs in
male and female forms. The female plant contains the highest concentrations of more
than 60 cannabinoids that are unique to the plant. Delta-9-tetrahydrocannabinol (Δ9THC) is the cannabinoid that is primarily responsible for the psychoactive effects of
cannabis. The most potent forms of cannabis come from the flowering tops of the plants
or from the dried, black–brown, resinous exudate from the leaves, which are referred to
as hashish or hash. The cannabis plant is usually cut, dried, chopped, and rolled into
cigarettes (commonly called “joints”), which are then smoked. The common names for
cannabis are marijuana, grass, pot, weed, tea, and Mary Jane. Other names, which
describe cannabis types of various strengths, are hemp, chasra, bhang, ganja, dagga,
and sinsemilla. The potency of marijuana preparations has increased in recent years
because of improved agricultural techniques used in cultivation so that plants may
contain up to 15 or 20 percent THC.
FIGURE 20.4-1
Marijuana (Cannabis sativa).
EPIDEMIOLOGY
Prevalence and Recent Trends
Based on the 2012 National Surveys on Drug Use and Health (NSDUH), an estimated 19
million persons age 12 years and older (7 percent) had used marijuana in the past
month. Of this age group, 2.4 million initiated use within the last year, 57 percent of
which initiated use before age 18 years.
The Monitoring the Future survey of adolescents in school indicates recent increases in
lifetime, annual, current (within the past 30 days), and daily use of marijuana by eighth
and tenth graders, continuing a trend that began in the early 1990s. In 1996, about 23
percent of eighth graders and about 40 percent of tenth graders reported having used
marijuana and, in 1998 and 1999, more than a quarter of marijuana initiates were aged
14 years or younger. The average age was 17. In 2012, approximately 1 percent of
eighth graders, 4 percent of tenth graders, and 7 percent of twelfth graders reported
daily use of marijuana.
Demographic Correlates
The rate of past year and current marijuana use by males was almost twice the rate for
females overall among those aged 26 and older. This gap between the sexes narrows
with younger users; at ages 12 to 17, there are no significant differences.
Race and ethnicity were also related to marijuana use, but the relationships varied by
age group. Among those aged 12 to 17, whites had higher rates of lifetime and past-year
marijuana use than blacks. Among those 17 to 34 years of age, whites reported higher
levels of lifetime use than blacks and Hispanics. But among those 35 and older, whites
and blacks reported the same levels of use. The lifetime rates for black adults were
significantly higher than those for Hispanics.
NEUROPHARMACOLOGY
As stated above, the principal component of cannabis is Δ9-THC; however, the cannabis
plant contains more than 400 chemicals, of which about 60 are chemically related to Δ9THC. In humans, Δ9-THC is rapidly converted into 11-hydroxy-Δ9-THC, the metabolite
that is active in the central nervous system (CNS).
A specific receptor for the cannabinols has been identified, cloned, and characterized.
The cannabinoid receptor, a member of the G-protein-linked family of receptors, is
linked to the inhibitory G protein (Gi), which is linked to adenylyl cyclase in an
inhibitory fashion. The cannabinoid receptor is found in highest concentrations in the
basal ganglia, the hippocampus, and the cerebellum, with lower concentrations in the
cerebral cortex (Figure 20.4-2). This receptor is not found in the brainstem, a fact
consistent with cannabis’s minimal effects on respiratory and cardiac functions. Studies
in animals have shown that the cannabinoids affect the monoamine and γ-aminobutyric
acid (GABA) neurons.
FIGURE 20.4-2
Autoradiography of cannabinoid receptor distribution in a sagittal section of rat brain.
Binding of tritiated ligand is dense in the hippocampus (Hipp), the globus pallidus (GP),
the entopeduncular nucleus (EP), the substantia nigra pars reticulata (SNr), and the
cerebellum (Cer). Binding is moderate in the cerebral cortex (Cx) and the caudate
putamen (CP) and sparse in the brainstem (Br St) and spinal cord. (From Howlett AC,
Bidaut-Russell M, Devane WA, Melvin LS, Johnson MR, Herkenham M. The cannabinoid
receptor: Biochemical anatomical, and behavioral characterization. Trends Neurosci.
1990;13:422, with permission.)
According to most studies, animals do not self-administer cannabinoids as they do
most other substances of abuse. Moreover, some debate questions whether the
cannabinoids stimulate the so-called reward centers of the brain, such as the
dopaminergic neurons of the ventral tegmental area. Tolerance to cannabis does
develop, however, and psychological dependence has been found, although the evidence
for physiological dependence is not strong. Withdrawal symptoms in humans are limited
to modest increases in irritability, restlessness, insomnia, and anorexia and mild nausea;
all these symptoms appear only when a person abruptly stops taking high doses of
cannabis.
When cannabis is smoked, the euphoric effects appear within minutes, peak in about
30 minutes, and last 2 to 4 hours. Some motor and cognitive effects last 5 to 12 hours.
Cannabis can also be taken orally when it is prepared in food, such as brownies and
cakes. About two to three times as much cannabis must be taken orally to be as potent
as cannabis taken by inhaling its smoke. Many variables affect the psychoactive
properties of cannabis, including the potency of the cannabis used, the route of
administration, the smoking technique, the effects of pyrolysis on the cannabinoid
content, the dose, the setting, and the user’s past experience, expectations, and unique
biological vulnerability to the effects of cannabinoids.
DIAGNOSIS AND CLINICAL FEATURES
The most common physical effects of cannabis are dilation of the conjunctival blood
vessels (red eye) and mild tachycardia. At high doses, orthostatic hypotension may
appear. Increased appetite—often referred to as “the munchies”—and dry mouth are
common effects of cannabis intoxication. That no clearly documented case of death
caused by cannabis intoxication alone reflects the substance’s lack of effect on the
respiratory rate. The most serious potential adverse effects of cannabis use are those
caused by inhaling the same carcinogenic hydrocarbons present in conventional
tobacco, and some data indicate that heavy cannabis users are at risk for chronic
respiratory disease and lung cancer. The practice of smoking cannabis-containing
cigarettes to their very ends, so-called “roaches,” further increases the intake of tar
(particulate matter). Many reports indicate that long-term cannabis use is associated
with cerebral atrophy, seizure susceptibility, chromosomal damage, birth defects,
impaired
immune
reactivity,
alterations
in
testosterone
concentrations,
and
dysregulation of menstrual cycles; these reports, however, have not been conclusively
replicated, and the association between these findings and cannabis use is uncertain.
Cannabis Use Disorder
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)
includes the diagnosis of cannabis use disorder. People who use cannabis daily over
weeks to months are most likely to become dependent. The risk of developing
dependence is around one in ten for anyone who uses cannabis. The earlier the age of
first use, the more often cannabis has been used, and the longer it has been used, the
higher the risk of dependence.
Cannabis Intoxication
Cannabis intoxication commonly heightens users’ sensitivities to external stimuli,
reveals new details, makes colors seem brighter and richer, and subjectively slows the
appreciation of time. In high doses, users may experience depersonalization and
derealization. Motor skills are impaired by cannabis use, and the impairment in motor
skills remains after the subjective, euphoriant effects have resolved. For 8 to 12 hours
after using cannabis, users’ impaired motor skills interfere with the operation of motor
vehicles and other heavy machinery. Moreover, these effects are additive to those of
alcohol, which is commonly used in combination with cannabis.
Mr. M was an unemployed 20-year-old man who lived with his parents. He was
brought to a hospital by some friends in a state of anxiety and agitation. He had been
out for the evening with some friends at a restaurant, and after a couple of beers, he
decided to have some cannabis. He had smoked cannabis on previous occasions;
however, this time he ate a lump of cannabis despite warnings from his friends. After
about half an hour, Mr. M appeared tense and anxious and complained that
everything was changing. He could see the faces of his friends increasing to about
three times their natural size. The room became distorted, and its proportions and
colors kept altering. He felt that the other guests in the restaurant were talking about
him and his friends in a menacing way, so he suddenly rushed outside because he felt
that he was in danger. He became increasingly agitated and started running down the
middle of the street, dodging in and out among the traffic. Eventually, his friends
were able to catch him. They were unable to quiet his anxiety, however, and had a
hard time persuading him to go with them to the hospital.
On examination Mr. M appeared tense and apprehensive, looking around the room
as if he felt uneasy with the surroundings, but he denied perceptual symptoms and did
not really believe that he was the subject of persecution. He was fully aware of his
surroundings, but his attention was fleeting, and he did not always answer questions.
There was no marked impairment of memory, and he was fully oriented.
Physical examination revealed conjunctival injection and an increased pulse rate of
120 beats per minute, but otherwise no abnormalities were found. Neurological
examination also revealed no abnormalities. In the course of a few hours, he quieted
down. When he felt recovered, he left the hospital with his friends.
Cannabis Intoxication Delirium
The delirium associated with cannabis intoxication is characterized by marked
impairment on cognition and performance tasks. Even modest doses of cannabis impair
memory, reaction time, perception, motor coordination, and attention. High doses that
also impair users’ levels of consciousness have marked effects on cognitive measures.
Cannabis Withdrawal
Studies have shown that cessation of use in daily cannabis users results in withdrawal
symptoms within 1 to 2 weeks of cessation. Withdrawal symptoms include irritability,
cannabis cravings, nervousness, anxiety, insomnia, disturbed or vivid dreaming,
decreased appetite, weight loss, depressed mood, restlessness, headache, chills, stomach
pain, sweating, and tremors.
Cannabis-Induced Psychotic Disorder
Cannabis-induced psychotic disorder is diagnosed in the presence of a cannabis-induced
psychosis. Cannabis-induced psychotic disorder is rare; transient paranoid ideation is
more common.
Florid psychosis is somewhat common in countries in which some persons have longterm access to cannabis of particularly high potency. The psychotic episodes are
sometimes referred to as “hemp insanity.” Cannabis use rarely causes a “bad-trip”
experience, which is often associated with hallucinogen intoxication. When cannabisinduced psychotic disorder does occur, it may be correlated with a preexisting
personality disorder in the affected person.
Cannabis-Induced Anxiety Disorder
Cannabis-induced anxiety disorder is a common diagnosis for acute cannabis
intoxication, which in many persons induces short-lived anxiety states often provoked
by paranoid thoughts. In such circumstances, panic attacks may be induced, based on illdefined and disorganized fears. The appearance of anxiety symptoms is correlated with
the dose and is the most frequent adverse reaction to the moderate use of smoked
cannabis. Inexperienced users are much more likely to experience anxiety symptoms
than are experienced users.
A 35-year-old white married male who was naïve to cannabis use was given two
“joints” by a friend. He smoked the first of the two in the same manner that he
normally smoked a cigarette (in about 3 to 5 minutes). Noting no major effects, he
proceeded immediately to smoke the second in the same amount of time. Within 30
minutes, he began to experience rapid heartbeat, dry mouth, mounting anxiety and
the delusional belief that his throat was closing up and that he was going to die. That
belief induced further panic and the patient was brought to the emergency room in
the midst of the experience. Reassurance that he would not die had no effect. He was
sedated with diazepam and some of his anxiety diminished. He eventually went to
sleep and on awakening in about 5 hours he was asymptomatic with full recall of
previous events.
Unspecified Cannabis-Related Disorders
DSM-5 includes the category unspecified cannabis-related disorders for cannabis
disorders that cannot be classified as cannabis use disorder, cannabis intoxication,
cannabis intoxication delirium, cannabis withdrawal, cannabis-induced psychotic
disorder, or cannabis-induced anxiety disorder. Cannabis intoxication can be associated
with depressive symptoms, although such symptoms may suggest long-term cannabis
use. Hypomania, however, is a common symptom in cannabis intoxication.
When either sleep disorder or sexual dysfunction symptoms are related to cannabis
use, they almost always resolve within days or a week after cessation of cannabis use.
Flashbacks.
There are case reports of persons who have experienced—at times
significantly—sensations related to cannabis intoxication after the short-term effects of
the substance have disappeared. Continued debate concerns whether flashbacks are
related to cannabis use alone or to the concomitant use of hallucinogens or of cannabis
tainted with phencyclidine (PCP).
Cognitive Impairment.
Clinical and experimental evidence indicates that the
long-term use of cannabis may produce subtle forms of cognitive impairment in the
higher cognitive functions of memory, attention, and organization and in the
integration of complex information. This evidence suggests that the longer the period of
heavy cannabis use, the more pronounced the cognitive impairment. Nonetheless,
because the impairments in performance are subtle, it remains to be determined how
significant they are for everyday functioning. It also remains to be investigated whether
these impairments can be reversed after an extended period of abstinence from
cannabis.
Amotivational Syndrome.
A controversial cannabis-related syndrome is
amotivational syndrome. Whether the syndrome is related to cannabis use or reflects
characterological traits in a subgroup of persons regardless of cannabis use is under
debate. Traditionally, the amotivational syndrome has been associated with long-term
heavy use and has been characterized by a person’s unwillingness to persist in a task—
be it at school, at work, or in any setting that requires prolonged attention or tenacity.
Persons are described as becoming apathetic and anergic, usually gaining weight, and
appearing slothful.
TREATMENT AND REHABILITATION
Treatment of cannabis use rests on the same principles as treatment of other substances
of abuse—abstinence and support. Abstinence can be achieved through direct
interventions, such as hospitalization, or through careful monitoring on an outpatient
basis by the use of urine drug screens, which can detect cannabis for up to 4 weeks after
use. Support can be achieved through the use of individual, family, and group
psychotherapies. Education should be a cornerstone for both abstinence and support
programs. A patient who does not understand the intellectual reasons for addressing a
substance-abuse problem has little motivation to stop. For some patients, an antianxiety
drug may be useful for short-term relief of withdrawal symptoms. For other patients,
cannabis use may be related to an underlying depressive disorder that may respond to
specific antidepressant treatment.
Medical Use of Marijuana
Marijuana has been used as a medicinal herb for centuries, and cannabis was listed in
the US Pharmacopeia until the end of the 19th century as a remedy for anxiety,
depression, and gastrointestinal disorders, among others. Currently, cannabis is a
controlled substance with a high potential for abuse and no medical use recognized by
the Drug Enforcement Agency (DEA); however, it is used to treat various disorders, such
as the nausea secondary to chemotherapy, multiple sclerosis (MS) chronic pain, acquired
immune deficiency syndrome (AIDS), epilepsy, and glaucoma. In 1996, California
residents approved the California Compensation Use Act that allowed state residents to
grow and use marijuana for these disorders: in 2001, however, the U.S. Supreme Court
ruled 8 to 0 that the manufacture and distribution of marijuana are illegal under any
circumstances. In addition, the Court held that patients using marijuana for medical
purposes can be prosecuted; however, as of 2013, 20 states—Alaska, Arizona,
California, Colorado, Connecticut, Delaware, Hawaii, Illinois, Maine, Massachusetts,
Michigan, Montana, Nevada, New Hampshire, New Jersey, New Mexico, Oregon, Rhode
Island, Vermont and Washington—and the District of Columbia have passed laws
exempting patients who use cannabis under a physician’s supervision from state
criminal penalties.
In addition to the Supreme Court ruling, periodically the federal government attempts to prosecute doctors who
prescribe the drug for medical use with the threat of loss of licensure or jail sentences. In a strongly worded editorial, the
New England Journal of Medicine urged that “Federal authorities should rescind their prohibition of the medical use of
marijuana for seriously ill patients and allow physicians to decide which patients to treat.” The editorial concluded by
commenting on the role of the physician: “Some physicians will have the courage to challenge the continued proscription
of marijuana for the sick. Eventually, their actions will force the courts to adjudicate between the rights of those at death’s
door and the absolute power of bureaucrats whose decisions are based more on reflexive ideology and political correctness
than on compassion.”
Dronabinol, a synthetic form of THC, has been approved by the U.S. Food and Drug
Administration (FDA); some researchers believe, however, that when taken orally, it is
not as effective as smoking the entire plant product. In 2006, regulatory officials
authorized the first U.S. clinical trial investigating the efficacy of Sativex, an oral spray
consisting of natural cannabis extracts, for the treatment of cancer pain. Sativex is
currently available by prescription in Canada and on a limited basis in Spain and Great
Britain for patients with neuropathic pain, multiple sclerosis, and other conditions.
Sativex can be prescribed in the United States only with a special exemption granted by
the FDA for use in certain patients. In 2013, a product called Epidiolex which contains
cannabidiol was granted orphan drug status for the treatment of certain rare,
intractable types of epilepsy in children.
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05 - 20.5 Hallucinogen Related Disorders
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20.5 Hallucinogen-Related Disorders
Hallucinogens, by definition, are intoxicants. The use of hallucinogenic drugs is
associated with panic attacks, hallucinogen persisting perception disorder (flashbacks),
psychosis, delirium, and mood and anxiety disorders. Hallucinogens have been used for
thousands of years, and drug-induced hallucinogenic states have been part of social and
religious rituals. The discovery of lysergic acid diethylamide (LSD) in 1943 increased the
use and misuse of hallucinogens because such synthetic hallucinogens are easily made,
easily distributed, sold cheaply, and much more potent than their botanical
counterparts. This paved the way to the abuse of synthetic hallucinogens and the
development of several associated psychiatric disorders that are now seen in psychiatric
practice.
PREPARATIONS
Hallucinogens are natural and synthetic substances that are variously called psychedelics
or psychotomimetics because, in addition to inducing hallucinations, they produce a loss
of contact with reality and an experience of expanded and heightened consciousness.
The hallucinogens are classified as Schedule I controlled substances; the US Food and
Drug Administration (FDA) has decreed that they have no medical use and a high abuse
potential.
The classic, naturally occurring hallucinogens are psilocybin (from some mushrooms)
and mescaline (from peyote cactus); others are harmine, harmaline, ibogaine, and
dimethyltryptamine (DMT). The classic synthetic hallucinogen is LSD, synthesized in
1938 by Albert Hoffman, who later accidentally ingested some of the drug and
experienced the first LSD-induced hallucinogenic episode. Some researchers classify the
substituted
or
so-called
designer
amphetamines,
such
as
3,4methylenedioxyamphetamine (MDMA), as hallucinogens. Because these drugs are
structurally related to amphetamines, this textbook classifies them as stimulant
substances, and they are covered in Section 20.9. Table 20.5-1 lists some representative
hallucinogens.
Table 20.5-1
Overview of Representative Hallucinogens
Phencyclidine (PCP; 1-1 [phenylcyclohexyl] piperidine), also known as angel dust, was
first developed as a novel anesthetic in the late 1950s. This drug and the closely related
compound ketamine were termed dissociative anesthetics, because they produced a
condition in which subjects were awake but apparently insensitive to, or dissociated
from, the environment. Phencyclidine and ketamine exert their unique behavioral
effects by blocking N-methyl-D-aspartate (NMDA)–type receptors for the excitatory
neurotransmitter glutamate. Their intoxication can present with a variety of symptoms,
from anxiety to psychosis. Phencyclidine and ketamine are classified as Schedule II and
Schedule III controlled substances, respectively. Although different in pharmacology and
clinical effects, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) includes PCP and ketamine within the hallucinogen category due to their
hallucinogenic effects.
EPIDEMIOLOGY
The incidence of hallucinogen use has exhibited two notable periods of increase.
Between 1965 and 1969, there was a tenfold increase in the estimated annual number of
initiates. This increase was driven primarily by the use of LSD. The second period of
increase in first-time hallucinogen use occurred from around 1992 until 2000, fueled
mainly by increases in use of ecstasy (i.e., MDMA). Decreases in initiation of both LSD
and ecstasy were evident between then and 2013, coinciding with an overall drop in
hallucinogen incidence from 1.6 million to 1.1 million.
The National Survey on Drug Use and Health (NSDUH) found that approximately 10
percent of persons age 12 years or older reported lifetime use of hallucinogens. Of this
group, 9 percent reported lifetime use of LSD, 6 percent reported lifetime use of ecstasy,
and 3 percent reported lifetime use of PCP. The highest rates of current use are among
18 to 25 year olds (2 percent) followed by 12 to 17 year olds (0.9 percent) and adults 25
years or older (0.2 percent). Males (9 percent) are more likely than females (11
percent) to use hallucinogens. Approximately 331,000 persons age 12 years or older
were dependent on or abused hallucinogens within the past year.
Hallucinogen use is most common among young (15 to 35 years of age) white men.
The ratio of whites to blacks who have used a hallucinogen is 2:1; the white to Hispanic
ratio is about 1.5:1. Men represent 62 percent of those who have used a hallucinogen at
some time and 75 percent of those who have used a hallucinogen in the preceding
month. Persons 26 to 34 years of age show the highest use of hallucinogens, with 16
percent having used a hallucinogen at least once. Persons 18 to 25 years of age have the
highest recent use of a hallucinogen.
Cultural factors influence the use of hallucinogens; their use in the western United
States is significantly higher than in the southern United States. Hallucinogen use is
associated with less morbidity and less mortality than use of some other substances. For
example, one study found that only 1 percent of substance-related emergency room
visits were related to hallucinogens, compared with 40 percent for cocaine-related
problems. Of persons visiting the emergency room for hallucinogen-related reasons,
however, more than 50 percent were younger than 20 years of age. Resurgence in the
popularity of hallucinogens has been reported.
Phencyclidine
Phencyclidine and some related substances are relatively easy to synthesize in illegal
laboratories and relatively inexpensive to buy on the street. The variable quality of the
laboratories, however, results in a range of potency and purity. PCP use varies most
markedly with geography. Most users of PCP also use other substances, particularly
alcohol, but also opiates, opioids, marijuana, amphetamines, and cocaine. PCP is
frequently added to marijuana, with severe untoward effects on users. The actual rate of
PCP dependence and abuse is not known, but PCP is associated with 3 percent of
substance abuse deaths and 32 percent of substance-related emergency room visits
nationally.
In the United States, 2.5 percent of those ages 12 and older acknowledged ever using
PCP. The highest lifetime prevalence was in those aged 26 to 34 years (4 percent),
whereas the highest proportion using PCP in the prior year (0.7 percent) was in those
aged 12 to 17 years.
Some areas of some cities have a tenfold higher usage rate of PCP than other areas.
The highest PCP use in the United States is in Washington, DC, where PCP accounts for
18 percent of all substance-related deaths and more than 1,000 emergency room visits
per year. In Los Angeles, Chicago, and Baltimore, the comparable figure is 6 percent.
Overall, most users are between 18 and 25 years of age and they account for 50 percent
of cases. Patients are more likely to be male rather than female, especially those who
visit emergency rooms. There are twice as many white as blacks users, although blacks
account for more visits to hospitals for PCP-related disorders than do whites. PCP use
appears to be rising, with some reports showing a 50 percent increase, particularly in
urban areas.
NEUROPHARMACOLOGY
Although most hallucinogenic substances vary in their pharmacological effects, LSD can
serve as a hallucinogenic prototype. The pharmacodynamic effect of LSD remains
controversial, although it is generally agreed that the drug acts on the serotonergic
system, either as an antagonist or as an agonist. Data at this time suggest that LSD acts
as a partial agonist at postsynaptic serotonin receptors.
Most hallucinogens are well absorbed after oral ingestion, although some are ingested
by inhalation, smoking, or intravenous injection. Tolerance for LSD and other
hallucinogens develops rapidly and is virtually complete after 3 or 4 days of continuous
use. Tolerance also reverses quickly, usually in 4 to 7 days. Neither physical dependence
nor withdrawal symptoms occur with hallucinogens, but a user can develop a
psychological dependence on the insight-inducing experiences of episodes of
hallucinogen use.
Phencyclidine
Phencyclidine and its related compounds are variously sold as a crystalline powder,
paste, liquid, or drug-soaked paper (blotter). PCP is most commonly used as an additive
to a cannabis- or parsley-containing cigarette. Experienced users report that the effects
of 2 to 3 mg of smoked PCP occur in about 5 minutes and plateau in 30 minutes. The
bioavailability of PCP is about 75 percent when taken by intravenous administration
and about 30 percent when smoked. The half-life of PCP in humans is about 20 hours,
and the half-life of ketamine in humans is about 2 hours.
The primary pharmacodynamic effect of PCP and ketamine is as an antagonist at the
NMDA subtype of glutamate receptors. PCP binds to a site within the NMDA-associated
calcium channel and prevents the influx of calcium ions. PCP also activates the
dopaminergic neurons of the ventral tegmental area, which project to the cerebral
cortex and the limbic system. Activation of these neurons is usually involved in
mediating the reinforcing qualities of PCP.
Tolerance for the effects of PCP occurs in humans, although physical dependence
generally does not occur. In animals that are administered more PCP per pound for
longer times than most humans, PCP does induce physical dependence, however, with
marked withdrawal symptoms of lethargy, depression, and craving. Physical symptoms
of withdrawal in humans are rare, probably as a function of dose and duration of use.
Although physical dependence on PCP is rare in humans, psychological dependence on
both PCP and ketamine are common, and some users become psychologically dependent
on the PCP-induced psychological state.
That PCP is made in illicit laboratories contributes to the increased likelihood of
impurities in the final product. One such contaminant is 1-piperidenocyclohexane
carbonitrite, which releases hydrogen cyanide in small quantities when ingested.
Another contaminant is piperidine, which can be recognized by its strong, fishy odor.
DIAGNOSIS
Hallucinogen Use Disorder
Long-term hallucinogen use is not common. Some long-term users of PCP are said to be
“crystallized,” a syndrome characterized by dulled thinking, decreased reflexes, loss of
memory, loss of impulse control, depression, lethargy, and impaired concentration.
Although psychological dependence occurs, it is rare, in part because each LSD
experience is different and in part because there is no reliable euphoria.
B, a 16-year-old boy from divorced parents, was admitted to the psychiatric unit of
a local hospital. He had slashed his wrists with a knife, severing nerves and tendons
in his left hand, and drifted in and out of consciousness during the night. He finally
contacted the mother of a friend who lived nearby in the morning who immediately
brought him to the hospital.
B had a history of juvenile delinquency from the age of 13 when he began hanging
out with some older boys at his junior high school. He and his friends shoplifted, stole,
smoked marijuana, and took LSD. B’s grades dropped and he got in trouble at school
on two occasions for getting into fights with other students.
On admission, B stated that he did not intend on committing suicide when he
slashed his wrist. After some questioning, he revealed that he had been “dropping
acid” with some friend and after they left he thought he heard the sirens of police cars
approaching his home. He did not wish to get arrested, so he slashed his wrist and
then lost consciousness. He denies feeling depressed, although he claims his life is
pointless and that he felt it made no difference whether he lived or died.
Hallucinogen Intoxication
Intoxication with hallucinogens is characterized by maladaptive behavioral and
perceptual changes and by certain physiological signs (Table 20.5-2). The differential
diagnosis for hallucinogen intoxication includes anticholinergic and amphetamine
intoxication and alcohol withdrawal. The preferred treatment for hallucinogen
intoxication is talking down the patient; during this process, guides can reassure
patients that the symptoms are drug induced, that they are not going crazy, and that the
symptoms will resolve shortly. In the most severe cases, dopaminergic antagonists—for
example, haloperidol (Haldol)—or benzodiazepines—for example, diazepam (Valium)—
can be used for a limited time. Hallucinogen intoxication usually lacks a withdrawal
syndrome.
Table 20.5-2
Physiological Changes from Hallucinogens
Short-term PCP intoxication can have potentially severe complications and must
often be considered a psychiatric emergency. Some patients may be brought to
psychiatric attention within hours of ingesting PCP, but often 2 to 3 days elapse
before psychiatric help is sought. Persons who lose consciousness are brought for help
earlier than those who remain conscious. Most patients recover completely within a
day or two, but some remain psychotic for as long as 2 weeks. Patients who are first
seen in a coma often exhibit disorientation, hallucinations, confusion, and difficulty
communicating on regaining consciousness. These symptoms may also be seen in
noncomatose patients, but their symptoms appear to be less severe than those of
comatose patients. Behavioral disturbances sometimes are severe; they can include
public masturbation, stripping off clothes, violence, urinary incontinence, crying, and
inappropriate laughing. Patients frequently have amnesia for the entire period of the
psychosis. A 17-year-old male patient was brought to the emergency room by the
police, having been found disoriented on the street. As the police attempted to
question him, he became increasingly agitated; when they attempted to restrain him,
he became assaultive. Attempts to question or to examine him in the emergency
department evoked increased agitation.
Initially, it was impossible to determine vital signs or to draw blood. Based on the
observation of horizontal, vertical, and rotator nystagmus, a diagnosis of PCP
intoxication was entertained. Within a few minutes of being placed in a darkened
examination room, his agitation markedly decreased. Blood pressure was 170/100;
other vital signs were within normal limits. Blood was drawn for toxicological
examination. The patient agreed to take 20 mg of diazepam (Valium) orally. Thirty
minutes later, he was less agitated and could be interviewed, although he responded
to questions in a fragmented fashion and was slightly dysarthic. He stated that he
must have inadvertently taken a larger-than-usual dose of “dust,” which he reported
having used once or twice a week for several years. He denied use of any other
substance and any history of mental disorder. He was disoriented to time and place.
The qualitative toxicology screen revealed PCP and no other drugs. Results of
neurological examination were within normal limits, but brisk deep tendon reflexes
were noted. Some 90 minutes after arrival, his temperature, initially normal, was
elevated to 38°C, his blood pressure had increased to 182/110, and he was poorly
responsive to stimulation. He was admitted to a medical bed. His blood pressure and
level of consciousness continued to fluctuate over the ensuing 18 hours. Results of
hematological and biochemical analyses of blood, as well as urinalyses, remained
within normal limits. A history obtained from his family revealed that the patient had
had multiple emergency room visits for complications from PCP use during the
previous several years. He had completed a 30-day residential treatment program and
had participated in several outpatient programs but had consistently relapsed. The
patient was discharged after vital signs and level of consciousness had been within
normal limits for 8 hours. At discharge, nystagmus and dysarthria were no longer
present. A referral to an outpatient treatment program was made. (Courtesy of Daniel
C. Javitt, M.D., Ph.D., and Stephen R. Zukin, M.D.)
Hallucinogen Persisting Perception Disorder
Long after ingesting a hallucinogen, a person can experience a flashback of
hallucinogenic symptoms. This syndrome is diagnosed as hallucinogen persisting
perception disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5). According to studies, from 15 to 80 percent of users of hallucinogens
report having experienced flashbacks. The differential diagnosis for flashbacks includes
migraine, seizures, visual system abnormalities, and posttraumatic stress disorder. The
following can trigger a flashback: emotional stress; sensory deprivation, such as
monotonous driving; or use of another psychoactive substance, such as alcohol or
marijuana.
Flashbacks are spontaneous, transitory recurrences of the substance-induced
experience. Most flashbacks are episodes of visual distortion, geometric hallucinations,
hallucinations of sounds or voices, false perceptions of movement in peripheral fields,
flashes of color, trails of images from moving objects, positive afterimages and halos,
macropsia, micropsia, time expansion, physical symptoms, or relived intense emotion.
The episodes usually last a few seconds to a few minutes, but sometimes last longer.
Most often, even in the presence of distinct perceptual disturbances, the person has
insight into the pathological nature of the disturbance. Suicidal behavior, major
depressive disorder, and panic disorders are potential complications.
A 20-year-old undergraduate presented with a chief complaint of seeing the air. The
visual disturbance consisted of perception of white pinpoint specks too numerous to
count in both the central and peripheral visual fields. They were constantly present
and were accompanied by the perception of trails of moving objects left behind as
they passed through the patient’s visual field. Attending a hockey game was difficult,
as the brightly dressed players left streaks of their own images against the white of
the ice for seconds at a time. The patient also described the false perception of
movement in stable objects, usually in his peripheral visual fields; halos around
objects; and positive and negative afterimages. Other symptoms included mild
depression, daily bitemporal headache, and a loss of concentration in the last year.
The visual syndrome had gradually emerged over the last 3 months following
experimentation with the hallucinogenic drug LCD-25 on three separate occasions. He
feared he had sustained some kind of “brain damage” from the drug experience. He
denied use of any other agents, including amphetamines, phencyclidine, narcotics, or
alcohol, to excess. He had smoked marijuana twice a week for a period of 7 months at
age 17.
The patient had consulted two ophthalmologists, both of whom confirmed that the
white pinpoint specks were not vitreous floaters (diagnostically insignificant
particulate matter floating in the vitreous humor of the eye that can cause the
perception of “specks”). A neurologist’s examination also proved negative. A
therapeutic trial of an anticonvulsant medication resulted in a 50 percent
improvement in the patient’s visual symptoms and remission of his depression.
Hallucinogen Intoxication Delirium
Hallucinogen intoxication delirium is a relatively rare disorder beginning during
intoxication in those who have ingested pure hallucinogens. An estimated 25 percent of
all PCP-related emergency room patients may meet the criteria for hallucinogen
intoxication delirium. Hallucinogens are often mixed with other substances, however,
and the other components or their interactions with the hallucinogens can produce
clinical delirium.
Hallucinogen-Induced Psychotic Disorders
If psychotic symptoms are present in the absence of retained reality testing, a diagnosis
of hallucinogen-induced psychotic disorder may be warranted. The most common
adverse effect of LSD and related substances is a “bad trip,” an experience resembling
the acute panic reaction to cannabis but sometimes more severe; a bad trip can
occasionally produce true psychotic symptoms. The bad trip generally ends when the
immediate effects of the hallucinogen wear off, but its course is variable. Occasionally, a
protracted psychotic episode is difficult to distinguish from a nonorganic psychotic
disorder. Whether a chronic psychosis after drug ingestion is the result of the drug
ingestion, is unrelated to the drug ingestion, or is a combination of both the drug
ingestion and predisposing factors is currently unanswerable.
Occasionally, the psychotic disorder is prolonged, a reaction thought to be most
common in persons with preexisting schizoid personality disorder and prepsychotic
personalities, an unstable ego balance, or much anxiety. Such persons cannot cope with
the perceptual changes, body-image distortions, and symbolic unconscious material
stimulated by the hallucinogen. The rate of previous mental instability in persons
hospitalized for LSD reactions is high. Adverse reactions occurred in the late 1960s when
LSD was being promoted as a self-prescribed psychotherapy for emotional crises in the
lives of seriously disturbed persons. Now that this practice is less frequent, prolonged
adverse reactions are less common.
A 22-year-old female photography student presented to the hospital with
inappropriate mood and bizarre thinking. She had no prior psychiatric history. Nine
days before admission, she ingested one or two psilocybin mushrooms. Following the
immediate ingestion, the patient began to giggle. She then described euphoria, which
progressed to auditory hallucinations and belief in the ability to broadcast her
thoughts on the media. Two days later she repeated the ingestion, and continued to
exhibit psychotic symptoms to the day of admission. When examined she heard voices
telling her she could be president, and reported the sounds of “lambs crying.” She
continued to giggle inappropriately, bizarrely turning her head from side to side
ritualistically. She continued to describe euphoria, but with an intermittent sense of
hopelessness in a context of thought blocking. Her self-description was “feeling
lucky.” She was given haloperidol, 10 mg twice a day, along with benztropine
(Cogentin) 1 mg three times a day and lithium carbonate (Eskalith) 300 mg twice a
day. On this regimen her psychosis abated after 5 days.
Hallucinogen-Induced Mood Disorder
Unlike cocaine-induced mood disorder and amphetamine-induced mood disorder, in
which the symptoms are somewhat predictable, mood disorder symptoms accompanying
hallucinogen abuse can vary. Abusers may experience manic-like symptoms with
grandiose delusions or depression-like feelings and ideas or mixed symptoms. As with
the hallucinogen-induced psychotic disorder symptoms, the symptoms of hallucinogeninduced mood disorder usually resolve once the drug has been eliminated from the
person’s body.
Hallucinogen-Induced Anxiety Disorder
Hallucinogen-induced anxiety disorder also varies in its symptom pattern, but few data
about symptom patterns are available. Anecdotally, emergency room physicians who
treat patients with hallucinogen-related disorders frequently report panic disorder with
agoraphobia. Anxiety is probably the most common symptom causing a PCP-intoxicated
person to seek help in an emergency room.
Unspecified Hallucinogen-Related Disorder
When a patient with a hallucinogen-related disorder does not meet the diagnostic
criteria for any of the standard hallucinogen-related disorders, the patient may be
classified as having unspecified hallucinogen-related disorder. DSM-5 does not have a
diagnostic category of hallucinogen withdrawal, but some clinicians anecdotally report
a syndrome with depression and anxiety after cessation of frequent hallucinogen use.
Such a syndrome may best fit the diagnosis of unspecified hallucinogen-related disorder.
CLINICAL FEATURES
Lsysergic Acid Diethylamide
A large class of hallucinogenic compounds with well-studied structure–activity
relationships is represented by the prototype LSD. LSD is a synthetic base derived from
the lysergic acid nucleus from the ergot alkaloids. That family of compounds was
discovered in rye fungus and was responsible for lethal outbreaks of St. Anthony’s fire in
the Middle Ages. The compounds are also present in morning glory seeds in low
concentrations. Many homologs and analogs of LSD have been studied. None of them
has potency exceeding that of LSD.
Physiological symptoms from LSD are typically few and relatively mild. Dilated
pupils, increased deep tendon motor reflexes and muscle tension, and mild motor
incoordination and ataxia are common. Increased heart rate, respiration, and blood
pressure are modest in degree and variable, as are nausea, decreased appetite, and
salivation.
The usual sequence of changes follows a pattern of somatic symptoms appearing first,
then mood and perceptual changes, and, finally, psychological changes, although effects
overlap and, depending on the particular hallucinogen, the time of onset and offset
varies. The intensity of LSD effects in a nontolerant user generally is proportional to
dose, with 25 μg as an approximate threshold dose.
The syndrome produced by LSD resembles that produced by mescaline, psilocybin, and
some of the amphetamine analogs. The major difference among LSD, psilocybin, and
mescaline is potency. A 1.5 μg/kg dose of LSD is roughly equivalent to 225 μg/kg of
psilocybin, which is equivalent to 5 mg/kg of mescaline. With mescaline, onset of
symptoms is slower and more nausea and vomiting occurs but in general, the perceptual
effects are more similar than different.
Tolerance, particularly to the sensory and other psychological effects, is evident as
soon as the second or third day of successive LSD use. Four to 6 days free of LSD are
necessary to lose significant tolerance. Tolerance is associated with frequent use of any
of the hallucinogens. Cross-tolerance among mescaline, psilocybin, and LSD occurs, but
not between amphetamine and LSD, despite the chemical similarity of amphetamine
and mescaline.
Previously distributed as tablets, liquid, powder, and gelatin squares, in recent years,
LSD has been commonly distributed as “blotter acid.” Sheets of paper are soaked with
LSD, and dried and perforated into small squares. Popular designs are stamped on the
paper. Each sheet contains as many as a few hundred squares; one square containing 30
to 75 μg of LSD is one chewed dose, more or less. Planned massive ingestion is
uncommon but massive ingestion happens by accident.
The onset of action of LSD occurs within an hour, peaks in 2 to 4 hours, and lasts 8 to
12 hours. The sympathomimetic effects of LSD include tremors, tachycardia,
hypertension, hyperthermia, sweating, blurring of vision, and mydriasis. Death caused
by cardiac or cerebrovascular pathology related to hypertension or hyperthermia can
occur with hallucinogenic use. A syndrome similar to neuroleptic malignant syndrome
has reportedly been associated with LSD. Death can also be caused by a physical injury
when LSD use impairs judgment about traffic or a person’s ability to fly, for example.
The psychological effects are usually well tolerated, but when persons cannot recall
experiences or appreciate that the experiences are substance induced, they may fear the
onset of insanity.
With hallucinogen use, perceptions become unusually brilliant and intense. Colors and textures seem to be richer,
contours sharpened, music more emotionally profound, and smells and tastes heightened. Synesthesia is common; colors
may be heard or sounds seen. Changes in body image and alterations of time and space perception also occur.
Hallucinations are usually visual, often of geometric forms and figures, but auditory and tactile hallucinations are
sometimes experienced. Emotions become unusually intense and may change abruptly and often; two seemingly
incompatible feelings may be experienced at the same time. Suggestibility is greatly heightened, and sensitivity or
detachment from other persons may arise. Other common features are a seeming awareness of internal organs, the
recovery of lost early memories, the release of unconscious material in symbolic form, and regression and the apparent
reliving of past events, including birth. Introspective reflection and feelings of religious and philosophical insight are
common. The sense of self is greatly changed, sometimes to the point of depersonalization, merging with the external
world, separation of self from body, or total dissolution of the ego in mystical ecstasy.
There is no clear evidence of a drastic personality change or chronic psychosis produced by long-term LSD use by
moderate users not otherwise predisposed to these conditions. Some heavy users of hallucinogens, however, may
experience chronic anxiety or depression and may benefit from a psychological or pharmacological approach that
addresses the underlying problem.
Many persons maintain that a single experience with LSD has given them increased creative capacity, new psychological
insight, relief from neurotic or psychosomatic symptoms, or a desirable change in personality. In the 1950s and 1960s,
psychiatrists showed great interest in LSD and related substances, both as potential models for functional psychosis and as
possible pharmacotherapeutic agents. The availability of these compounds to researchers in the basic neurosciences has
led to many scientific advances.
Phenethylamines
Phenethylamines are compounds with chemical structures similar to those of the
neurotransmitters
dopamine
and
norepinephrine.
Mescaline
(3,4,5trimethoxyphenethylamine), a classic hallucinogen in every sense of the term, was the
first hallucinogen isolated from the peyote cactus that grows in the southwestern United
States and northern Mexico. Mescaline human pharmacology was characterized in 1896
and its structure verified by synthesis 23 years later. Although many psychoactive plants
have been recognized dating to before recorded history, mescaline was the only
structurally identified hallucinogen until LSD was described in 1943.
Mescaline
Mescaline is usually consumed as peyote “buttons,” picked from the small blue-green
cacti Lophophora williamsii and Lophophora diffusa. The buttons are the dried, round,
fleshy cacti tops. Mescaline is the active hallucinogenic alkaloid in the buttons. Use of
peyote is legal for the Native American Church members in some states. Adverse
reactions to peyote are rare during structured religious use. Peyote usually is not
consumed casually because of its bitter taste and sometimes severe nausea and vomiting
that precede the hallucinogenic effects.
Many structural variations of mescaline have been investigated and structural activity
relationships
fairly
well
characterized.
One
analog,
2,5-dimethoxy-4methylamphetamine (DOM), also known as STP, an unusually potent amphetamine
with hallucinogen properties, had a relatively brief period of illicit popularity and
notoriety in the 1960s, but it appears to have disappeared from the illicit market.
Another series of phenethylamine analogs with hallucinogenic properties is the 3,4methylenedioxyamphetamine (MDA)–related amphetamines. The currently most
popular and, to society, most troublesome member of this large family of drugs is
MDMA, or ecstasy, more a relatively mild stimulant than hallucinogen. MDMA produces
an altered state of consciousness with sensory changes and, most important for some
users, a feeling of enhanced personal interactions.
Many plants contain N,N-dimethyltryptamine (DMT), which is also found normally in
human biofluids at very low concentrations. When DMT is taken parenterally or by
sniffing, a brief, intense hallucinogenic episode can result. As with mescaline in the
phenethylamine group, DMT is one of the oldest, best documented, but least potent of
the tryptamine hallucinogens. Synthesized homologs of DMT have been evaluated in
humans and structure activity relationships have been reasonably well described.
Psilocybin Analogs
An unusual collection of tryptamines has its origin in the world of fungi. The natural
prototype is psilocybin itself. That and related homologs have been found in as many as
100 species of mushroom, largely of the Psilocybe genus.
Psilocybin is usually ingested as mushrooms. Many species of psilocybin-containing
mushrooms are found worldwide. In the United States, large Psilocybe cubensis (gold
caps) grow in Florida and Texas and are easily grown with cultivation kits advertised in
drug-oriented magazines and on the Internet. The tiny Psilocybe semilanceata (liberty
cap) grows in lawns and pastures in the Pacific Northwest. Psilocybin remains active
when the mushrooms are dried or cooked into omelets or other foods.
Psilocybin mushrooms are used in religious activities by Mexican Indians. They are
valued in Western society by users who prefer to ingest a mushroom rather than a
synthetic chemical. Of course, one danger of eating wild mushrooms is misidentification
and ingestion of a poisonous variety. At a large American university, 24 percent of
students reported using psychedelic mushrooms or mescaline, compared with 17 percent
who reported LSD use. Psilocybin sold as pills or capsules usually contains phencyclidine
(PCP) or LSD instead.
Studies are underway in several medical centers in the United States (including New
York University) to examine the use of psilocybin in terminally ill patients.
Preliminary reports indicate that the psilocybin is helpful in reducing morbid anxiety
about death and dying. It may play an important role in palliative care medicine in the
future.
Phencyclidine
The amount of PCP varies greatly from PCP-laced cigarette to cigarette; 1 g may be used
to make as few as four or as many as several dozen cigarettes. Less than 5 mg of PCP is
considered a low dose, and doses above 10 mg are considered high. Dose variability
makes it difficult to predict the effect, although smoking PCP is the easiest and most
reliable way for users to titrate the dose.
Persons who have just taken PCP are frequently uncommunicative, appear to be
oblivious, and report active fantasy production. They experience speedy feelings,
euphoria, bodily warmth, tingling, peaceful floating sensations, and, occasionally,
feelings of depersonalization, isolation, and estrangement. Sometimes, they have
auditory and visual hallucinations. They often have striking alterations of body image,
distortions of space and time perception, and delusions. They may experience
intensified dependence feelings, confusion, and disorganization of thought. Users may
be sympathetic, sociable, and talkative at one moment but hostile and negative at
another. Anxiety is sometimes reported; it is often the most prominent presenting
symptom during an adverse reaction. Nystagmus, hypertension, and hyperthermia are
common effects of PCP. Head-rolling movements, stroking, grimacing, muscle rigidity
on stimulation, repeated episodes of vomiting, and repetitive chanting speech are
sometimes observed.
The short-term effects last 3 to 6 hours and sometimes give way to a mild depression
in which the user becomes irritable, somewhat paranoid, and occasionally belligerent,
irrationally assaultive, suicidal, or homicidal. The effects can last for several days. Users
sometimes find that it takes 1 to 2 days to recover completely; laboratory tests show
that PCP can remain in the patient’s blood and urine for more than a week.
Ketamine
Ketamine is a dissociative anesthetic agent, originally derived from PCP, which is
available for use in human and veterinary medicine. It has become a drug of abuse, with
sources exclusively from stolen supplies. It is available as a powder or in solution for
intranasal, oral, inhalational, or (rarely) intravenous use. Ketamine functions by
working at the NMDA receptor and, as with PCP, can cause hallucinations and a
dissociated state in which the patient has an altered sense of the body and reality and
little concern for the environment.
Ketamine causes cardiovascular stimulation and no respiratory depression. On
physical examination, the patient may be hypertensive and tachycardic, have increased
salivation and bidirectional or rotary nystagmus, or both. The onset of action is within
seconds when used intravenously, and analgesia lasting 40 minutes and dissociative
effects lasting for hours have been described. Cardiovascular status should be monitored
and supportive care administered. A dystonic reaction has been described, as have
flashbacks, but a more common complication is related to a lack of concern for the
environment or personal safety.
Ketamine has a briefer duration of effect than PCP. Peak ketamine levels occur
approximately 20 minutes after intramuscular injection. After intranasal administration,
the duration of effect is approximately 1 hour. Ketamine is N-demethylated by liver
microsomal cytochrome P450 (CYP), especially CYP3A, into norketamine. Ketamine,
norketamine, and dehydronorketamine can be detected in urine, with half-lives of 3, 4,
and 7 hours, respectively. Urinary ketamine and norketamine levels vary widely from
individual to individual and can range from 10 to 7,000 ng/mL after intoxication. As of
yet, the relationship between serum ketamine levels and clinical symptoms has not been
formally studied. Ketamine is often used in combination with other drugs of abuse,
especially cocaine. Ketamine does not appear to interfere with, and may enhance,
cocaine metabolism. Ketamine is being studied for use in the treatment of depression.
ADDITIONAL HALLUCINOGENS
Canthinones
Canthinones are alkaloids similar to amphetamines naturally found in the khat plant and synthetically made and known as
“bath salts.” They are CNS stimulants that cause a massive release of dopamine, and a single dose can last up to 8 hours.
They produce profound toxic effects that can lead to seizures, strokes, and/or death. Hallucinations and delusions are
common. They are swallowed, injected, or “snorted” to produce the desired euphoric effect.
Ibogaine
Ibogaine is a complex alkaloid found in the African shrub Tabernanthe iboga. Ibogaine is a hallucinogen at the 400 mg dose
range. The plant originates in Africa and traditionally is used in sacramental initiation ceremonies. Although it has not been
a popular hallucinogen because of its unpleasant somatic effects when taken at hallucinogenic doses, patients exposed to
ibogaine may be encountered by a psychiatrist because of the therapeutic claims.
Ayahuasca
Ayahuasca, much discussed on Internet hallucinogen websites, originally referred to a decoction from one or more South
American plants. The substance contains the alkaloids harmaline and harmine. Both of those β-carboline alkaloids have
hallucinogenic properties, but the resulting visual sensory alterations are accompanied by considerable nausea. Amazon
native tribes discovered that adding leaves from plants containing substantial amounts of DMT markedly enhanced the
visual and sacramental impact of ayahuasca. Thus, neither component in the ayahuasca plant mixture works well alone
but when taken in combination an extremely effective hallucinogenic agent results.
In recent years, the term ayahuasca has evolved to a less specific term to refer to any mixture of two things that are
hallucinogenic when taken in combination. For example, harmine and harmaline are available as fine chemicals and when
taken along with many botanicals containing DMT result in a mixture with hallucinogen properties, initially intense but
usually of brief duration.
Salvia Divinorum
American Indians in northern Oaxaca, Mexico, have used Salvia divinorum as a medicine and as a sacred sacrament, which
is now widely discussed, advertised, and sold on the Internet. When the plant is chewed or dried leaves smoked, it
produces hallucinogen effects. Salvinorin-A, an active component in the plant, is parenterally potent, active at 250-μg doses
when smoked, and of scientific and potential medical interest because it binds to the opioid κ-receptor.
TREATMENT
Hallucinogen Intoxication
A basic principle in treatment is providing reassurance and supportive care. Patients
experiencing intense and unpleasant hallucinogen intoxication can be helped by a quiet
environment, verbal reassurance, and the passage of time. More rapid relief of intense
anxiety is likely after oral administration of 20 mg of diazepam (Valium) or, if oral
administration presents problems, an equivalent parenteral dose of a benzodiazepine.
Anxiety and other symptoms generally diminish within 20 minutes of medication
administration, compared to hours with only psychological and environmental support;
however, perceptual symptoms may persist. Patients may need gentle restraint if they
are in danger to themselves or others, but restraints should be avoided if possible.
Neuroleptic medications, particularly if given at excessive doses, may worsen symptoms
and are best avoided unless the diagnosis remains unclear and behavior cannot
otherwise be managed. The marketing of lower doses of LSD and a more sophisticated
approach to treatment of casualties by drug users themselves have combined to reduce
the appearance of this once-common disorder in psychiatric treatment facilities.
Hallucinogen Persisting Disorder
Treatment for hallucinogen persisting perception disorder is palliative. The first step in
the process is correct identification of the disorder; it is not uncommon for the patient to
consult a number of specialists before the diagnosis is made. Pharmacological
approaches include long-lasting benzodiazepines, such as clonazepam (Klonopin) and,
to a lesser extent, anticonvulsants including valproic acid (Depakene) and
carbamazepine (Tegretol). Currently, no drug is completely effective in ablating
symptoms. Antipsychotic agents should be used only in the treatment of hallucinogeninduced psychoses, because they may have a paradoxical effect and exacerbate
symptoms. A second dimension of treatment is behavioral. The patient must be
instructed to avoid gratuitous stimulation in the form of over-the-counter drugs,
caffeine, and alcohol, and avoidable physical and emotional stressors. Marijuana smoke
is a particularly strong intensifier of the disorder, even when passively inhaled. Finally,
three comorbid conditions are associated with hallucinogen persisting perception
disorder: panic disorder, major depression, and alcohol dependence. All these conditions
require primary prevention and early intervention.
Hallucinogen-Induced Psychosis
Treatment of hallucinogen-induced psychosis does not differ from conventional
treatment for other psychoses. In addition to antipsychotic medications, a number of
agents are reportedly effective, including lithium carbonate, carbamazepine, and
electroconvulsive therapy. Antidepressant drugs, benzodiazepines, and anticonvulsant
agents may each have a role in treatment as well. One hallmark of this disorder is that,
as opposed to schizophrenia, in which negative symptoms and poor interpersonal
relatedness may commonly be found, patients with hallucinogen-induced psychosis
exhibit the positive symptoms of hallucinations and delusions while retaining the ability
to relate to the psychiatrist. Medical therapies are best applied in a context of
supportive, educational, and family therapies. The goals of treatment are the control of
symptoms, a minimal use of hospitals, daily work, the development and preservation of
social relationships, and the management of comorbid illnesses such as alcohol
dependence.
Phencyclidine
Treatment of PCP intoxication aims to reduce systemic PCP levels and to address
significant medical, behavioral, and psychiatric issues. For intoxication and PCP-induced
psychotic disorder, although resolution of current symptoms and signs is paramount, the
long-term goal of treatment is to prevent relapse to PCP use. PCP levels can fluctuate
over many hours or even days, especially after oral administration. A prolonged period
of clinical observation is therefore mandatory before concluding that no serious or lifethreatening complications will ensue.
Trapping of ionized PCP in the stomach has led to the suggestion of continuous
nasogastric suction as a treatment for PCP intoxication. This strategy, however, can be
needlessly intrusive and can induce electrolyte imbalances. Administration of activated
charcoal is safer, and it binds PCP and diminishes toxic effects of PCP in animals.
Trapping of ionized PCP in urine has led to the suggestion of urinary acidification as
an aid to drug elimination. This strategy, however, may be ineffective and is potentially
dangerous. Only a small portion of PCP is excreted in urine, metabolic acidosis itself
carries significant risks, and acidic urine can increase the risk of renal failure secondary
to rhabdomyolysis. Because of the extremely large volume of distribution of PCP, neither
hemodialysis nor hemoperfusion can significantly promote drug clearance.
No drug is known to function as a direct PCP antagonist. Any compound binding to
the PCP receptor, which is located within the ion channel of the NMDA receptor, would
block NMDA receptor–mediated ion fluxes as does PCP itself. NMDA-receptor
mechanisms predict that pharmacological strategies promoting NMDA receptor
activation (e.g., administration of a glycine site agonist drug) would promote rapid
dissociation of PCP from its binding sites. No clinical trials of NMDA agonists for PCP or
ketamine intoxication in humans have been carried out to date. Treatment must
therefore be supportive and directed at specific symptoms and signs of toxicity. Classic
measures should be used for medical crises, including seizures, hypothermia, and
hypertensive crisis.
Because PCP disrupts sensory input, environmental stimuli can cause unpredictable,
exaggerated, distorted, or violent reactions. A cornerstone of treatment, therefore, is
minimization of sensory inputs to PCP-intoxicated patients. Patients should be evaluated
and treated in an environment that is as quiet and isolated as possible. Precautionary
physical restraint is recommended by some authorities, with the risk of rhabdomyolysis
from struggle against the restraints balanced by the avoidance of violent or disruptive
behavior. Pharmacological sedation can be accomplished with oral or intramuscular
(IM) antipsychotics or benzodiazepines; no convincing evidence indicates that either
class of compounds is clinically superior. Because of the anticholinergic actions of PCP
at high doses, neuroleptics with potent intrinsic anticholinergic properties should be
avoided.
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Catts VS, Catts SV. Psychotomimetic effects of PCP, LSD, and ecstasy: Pharmacological models of schizophrenia? In:
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Addictive Disord. 2013;32:150.
Fantegrossi WE, Murnane KS, Reissig CJ. The behavioral pharmacology of hallucinogens. Biochem Pharmacol. 2008;75:17.
Fontanilla D, Johannessen D, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE. The hallucinogen N,N-dimethyltryptamine
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2009:1387.
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06 - 20.6 Inhalant Related Disorders
20.6 Inhalant-Related Disorders
Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:1331.
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20.6 Inhalant-Related Disorders
Inhalant drugs (also called volatile substances or solvents) are volatile hydrocarbons that
vaporize to gaseous fumes at room temperature and are inhaled through the nose or
mouth to enter the bloodstream via the transpulmonary route. These compounds are
commonly found in many household products and are divided into four commercial
classes: (1) solvents for glues and adhesives; (2) propellants (e.g., for aerosol paint
sprays, hair sprays, and shaving cream); (3) thinners (e.g., for paint products and
correction fluids); and (4) fuels (e.g., gasoline, propane). These drugs are believed to
share some similar pharmacological properties despite their chemical differences.
Persons, especially adolescents, like to inhale these products for their intoxicating
effect. Inhalants are associated with a number of problems including conduct disorder,
mood disorders, suicidality, and physical and sexual abuse or neglect. In some cases, an
early time-limited use of inhalants may signal a lifelong problem with externalizing
behaviors and risk-taking propensity. A smaller subgroup use inhalants chronically and
such use has been associated with multiple sequelae, including major behavioral and
organ pathology from the drugs’ toxicity.
The fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-5) excludes anesthetic gases (e.g., nitrous
oxide and ether) and short-acting vasodilators (e.g., amyl nitrite) from the inhalant-related disorders, which are classified
as other (or unknown) substance-related disorders and are discussed in Section 20.12.
EPIDEMIOLOGY
Inhalant substances are easily available, legal, and inexpensive. These three factors
contribute to the high use of inhalants among poor persons and young persons.
Approximately 6 percent of persons in the United States had used inhalants at least
once, and about 1 percent of persons are current users. Among young adults 18 to 25
years of age, 11 percent had used inhalants at least once, and 2 percent were current
users. Among adolescents 12 to 17 years of age, 7 percent had used inhalants at least
once, and 1.1 percent were current users. In one study of high school seniors, 18 percent
reported having used inhalants at least once, and 2.7 percent reported having used
inhalants within the preceding month. White users of inhalants are more common than
either black or Hispanic users. Most users (up to 80 percent) are male. Some data
suggest that inhalant use may be more common in suburban communities in the United
States than in urban communities.
Inhalant use accounts for 1 percent of all substance-related deaths and less than 0.5 percent of all substance-related
emergency room visits. About 20 percent of the emergency room visits for inhalant use involve persons younger than 18
years of age. Inhalant use among adolescents may be most common in those whose parents or older siblings use illegal
substances. Inhalant use among adolescents is also associated with an increased likelihood of conduct disorder or antisocial
personality disorder.
NEUROPHARMACOLOGY
Inhalants most used by American adolescents are (in descending order) gasoline, glue
(which usually contains toluene), spray paint, solvents, cleaning fluids, and assorted
other aerosols. Sniffing vapor through the nose or huffing (taking deep breaths) through
the mouth leads to transpulmonary absorption with very rapid drug access to the brain.
Breathing through a solvent-soaked cloth, inhaling fumes from a glue-containing bag,
huffing vapor sprayed into a plastic bag, or breathing vapor from a gasoline can are
common. Approximately 15 to 20 breaths of 1 percent gasoline vapor produce several
hours of intoxication. Inhaled toluene concentrations from a glue-containing bag may
reach 10,000 ppm, and vapors from several tubes of glue may be inhaled each day. By
comparison, one study of just 100 ppm of toluene showed that a 6-hour exposure
produced a temporary neuropsychological performance decrement of approximately 10
percent.
Inhalants generally act as a central nervous system (CNS) depressant. Tolerance for
inhalants can develop, although withdrawal symptoms are usually fairly mild.
Inhalants are rapidly absorbed through the lungs and rapidly delivered to the brain.
The effects appear within 5 minutes and can last for 30 minutes to several hours,
depending on the inhalant substance and the dose. The concentrations of many inhalant
substances in blood are increased when used in combination with alcohol, perhaps
because of competition for hepatic enzymes. Although about one fifth of an inhalant
substance is excreted unchanged by the lungs, the remainder is metabolized by the liver.
Inhalants are detectable in the blood for 4 to 10 hours after use, and blood samples
should be taken in the emergency room when inhalant use is suspected.
Much like alcohol, inhalants have specific pharmacodynamic effects that are not well
understood. Because their effects are generally similar and additive to the effects of
other CNS depressants (e.g., ethanol, barbiturates, and benzodiazepines), some
investigators have suggested that inhalants operate by enhancing the γ-aminobutyric
acid (GABA) system. Other investigators have suggested that inhalants work through
membrane fluidization, which has also been hypothesized to be a pharmacodynamic
effect of ethanol.
DIAGNOSIS
Inhalant Use Disorder
Most persons probably use inhalants for a short time without developing a pattern of
long-term use resulting in dependence and abuse. Nonetheless, dependence and abuse of
inhalants occur and are diagnosed according to the DSM-5 (see page 621).
Inhalant Intoxication
The diagnostic criteria for inhalant intoxication specify the presence of maladaptive
behavioral changes and at least two physical symptoms. The intoxicated state is often
characterized by apathy, diminished social and occupational functioning, impaired
judgment, and impulsive or aggressive behavior, and it can be accompanied by nausea,
anorexia, nystagmus, depressed reflexes, and diplopia. With high doses and long
exposures, a user’s neurological status can progress to stupor and unconsciousness, and
a person may later be amnestic for the period of intoxication. Clinicians can sometimes
identify a recent user of inhalants by rashes around the patient’s nose and mouth;
unusual breath odors; the residue of the inhalant substances on the patient’s face, hands,
or clothing; and irritation of the patient’s eyes, throat, lungs, and nose. The disorder can
be chronic, as in the following case.
A 16-year-old single Hispanic female was referred to a university substancetreatment program for evaluation. The patient had been convicted for auto theft,
menacing with a weapon, and being out of control by her family. By age 15, she had
regularly been using inhalants and drinking alcohol heavily. She had tried typewritererasing fluid, bleach, tile cleaner, hairspray, nail polish, glue, and gasoline, but
preferred spray paint. She had sniffed paint many times each day for about 6 months
at age 15, using a maximum of eight paint cans per day. The patient said, “It blacks
out everything.” Sometimes she had lost consciousness, and she believed that the paint
had impaired her memory and made her “dumb.” (Courtesy of Thomas J. Crowley,
M.D.)
Inhalant Intoxication Delirium
Delirium can be induced by the effects of the inhalants themselves, by
pharmacodynamic interactions with other substances, and by the hypoxia that may be
associated with either the inhalant or its method of inhalation. If the delirium results in
severe behavioral disturbances, short-term treatment with a dopamine receptor
antagonist, such as haloperidol (Haldol), may be necessary. Benzodiazepines should be
avoided because of the possibility of increasing the patient’s respiratory depression.
Inhalant-Induced Persisting Dementia
Inhalant-induced persisting dementia, as with delirium, may result from the neurotoxic
effects of the inhalants themselves; the neurotoxic effects of the metals (e.g., lead)
commonly used in inhalants; or the effects of frequent and prolonged periods of
hypoxia. The dementia caused by inhalants is likely to be irreversible in all but the
mildest cases.
Inhalant-Induced Psychotic Disorder
Clinicians can specify hallucinations or delusions as the predominant symptoms.
Paranoid states are probably the most common psychotic syndromes during inhalant
intoxication.
Inhalant-Induced Mood Disorder and Inhalant-Induced Anxiety Disorder
Inhalant-induced mood disorder and inhalant-induced anxiety disorder allow the
classification of inhalant-related disorders characterized by prominent mood and anxiety
symptoms. Depressive disorders are the most common mood disorders associated with
inhalant use, and panic disorders and generalized anxiety disorder are the most common
anxiety disorders.
Other Inhalant-Induced Disorders
Other Inhalant-Induced Disorder is the recommended DSM-5 diagnosis for inhalantrelated disorders that do not fit into one of the diagnostic categories discussed earlier.
CLINICAL FEATURES
In small initial doses, inhalants can be disinhibiting and produce feelings of euphoria
and excitement as well as pleasant floating sensations, the effects for which persons
presumably use the drugs. High doses of inhalants can cause psychological symptoms of
fearfulness, sensory illusions, auditory and visual hallucinations, and distortions of body
size. The neurological symptoms can include slurred speech, decreased speed of talking,
and ataxia. Long-term use can be associated with irritability, emotional lability, and
impaired memory.
Tolerance for the inhalants does develop for some users; a withdrawal syndrome can
accompany the cessation of inhalant use. The withdrawal syndrome does not occur
frequently; when it does, it can be characterized by sleep disturbances, irritability,
jitteriness, sweating, nausea, vomiting, tachycardia, and (sometimes) delusions and
hallucinations.
Organ Pathology and Neurological Effects
Inhalants are associated with many potentially serious adverse effects. The most serious
of these is death, which can result from respiratory depression, cardiac arrhythmias,
asphyxiation, aspiration of vomitus, or accident or injury (e.g., driving while intoxicated
with inhalants). Placing an inhalant-soaked rag and one’s head into a plastic bag, a
common procedure for inhalant users, can cause coma and suffocation.
Chronic inhalant users may have numerous neurological problems. Computed
tomography (CT) and magnetic resonance imaging (MRI) reveal diffuse cerebral,
cerebellar, and brainstem atrophy with white matter disease, a leukoencephalopathy.
Single photon emission CT (SPECT) of former solvent-abusing adolescents showed both
increases and decreases of blood flow in different cerebral areas. Several studies of
house painters and factory workers who have been exposed to solvents for long periods
also have found evidence of brain atrophy on CT scans, with decreased cerebral blood
flow.
Neurological and behavioral signs and symptoms can include hearing loss, peripheral
neuropathy, headache, paresthesias, cerebellar signs, persisting motor impairment,
parkinsonism, apathy, poor concentration, memory loss, visual-spatial dysfunction,
impaired processing of linguistic material, and lead encephalopathy. White matter
changes, or pontine atrophy on MRI, have been associated with worse intelligence
quotient (IQ) test results. The combination of organic solvents with high concentrations
of copper, zinc, and heavy metals has been associated with the development of brain
atrophy, temporal lobe epilepsy, decreased IQ, and a variety of electroencephalography
(EEG) changes.
Other serious adverse effects associated with long-term inhalant use include
irreversible hepatic disease or renal damage (tubular acidosis) and permanent muscle
damage
associated
with
rhabdomyolysis.
Additional
adverse
effects
include
cardiovascular and pulmonary symptoms (e.g., chest pain and bronchospasm) as well as
gastrointestinal (GI) symptoms (e.g., pain, nausea, vomiting, and hematemesis). There
are several clinical reports of toluene embryopathy, with signs such as those of fetal
alcohol syndrome. These include low birth weight, microcephaly, shortened palpebral
fissures, small face, low-set ears, and other dysmorphic signs. These babies reportedly
develop slowly, show hyperactivity, and have cerebellar dysfunction. No convincing
evidence indicates, however, that toluene, the best-studied inhalant, produces genetic
damage in somatic cells.
TREATMENT
Inhalant intoxication, as with alcohol intoxication, usually requires no medical attention
and resolves spontaneously. However, effects of the intoxication, such as coma,
bronchospasm, laryngospasm, cardiac arrhythmias, trauma, or burns, need treatment.
Otherwise, care primarily involves reassurance, quiet support, and attention to vital
signs and level of consciousness. Sedative drugs, including benzodiazepines, are
contraindicated because they worsen inhalant intoxication.
No established treatment exists for the cognitive and memory problems of inhalantinduced persisting dementia. Street outreach and extensive social service support have
been offered to severely deteriorated, inhalant-dependent, homeless adults. Patients
may require extensive support within their families or in foster or domiciliary care.
The course and treatment of inhalant-induced psychotic disorder are like those of
inhalant intoxication. The disorder is brief, lasting a few hours to (at most) a very few
weeks beyond the intoxication. Appropriate is vigorous treatment of such lifethreatening complications as respiratory or cardiac arrest, together with conservative
management of the intoxication itself. Confusion, panic, and psychosis mandate special
attention to patient safety. Severe agitation may require cautious control with
haloperidol (5 mg intramuscularly per 70 kg body weight). Sedative drugs should be
avoided because they may aggravate the psychosis. Inhalant-induced anxiety and mood
disorders may precipitate suicidal ideation, and patients should be carefully evaluated
for that possibility. Antianxiety medications and antidepressants are not useful in the
acute phase of the disorder; they may be of use in cases of a coexisting anxiety or
depressive illness.
Day Treatment and Residential Programs
Day treatment and residential programs have been used successfully, especially for
adolescent abusers with combined substance dependence and other psychiatric disorders.
Treatment addresses the comorbid state which, in most cases, is conduct disorder or, in
other instances, may be attention-deficit/hyperactivity disorder (ADHD), major
depressive disorder, dysthymic disorder, and posttraumatic stress disorder (PTSD).
Attention is also directed to experiences of abuse or neglect, which is very common in
these patients. Both group and individual therapy are used that are behaviorally
oriented, with immediate rewards for progress toward objectively defined goals in
treatment and punishments for lapses to previous behaviors. Patients attend on-site
schools with special education teachers, together with planned recreational activities,
and the programs provide birth control consultations. The patients’ families, often very
chaotic, are engaged in modifications of structural family therapy or multisystemic
therapy, both of which have good empirical support. Participation in 12-step programs
is required. Treatment interventions are coordinated closely with interventions by
community social workers and probation officers. Progress is monitored with urine and
breath samples analyzed for alcohol and other drugs at intake and frequently during
treatment.
Treatment usually lasts 3 to 12 months. Termination is considered successful if the
youth has practiced a plan to stay abstinent; is showing fewer antisocial behaviors; has
a plan to continue any needed psychiatric treatment (e.g., treatment for comorbid
depression); has a plan to live in a supportive, drug-free environment; is interacting
with the family in a more productive way; is working or attending school; and is

07 - 20.7 Opioid Related Disorders
20.7 Opioid-Related Disorders
associating with drug-free, nondelinquent peers.
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20.7 Opioid-Related Disorders
Opioids have been used for analgesic and other medicinal purposes for thousands of
years, but they also have a long history of misuse for their psychoactive effects.
Continued opioid misuse can result in syndromes of abuse and dependence and cause
disturbances in mood, behavior, and cognition that can mimic other psychiatric
disorders. In developed countries, the opioid drug most frequently associated with abuse
and dependence is heroin; however, there is growing public health concern about
prescription opioids, which are widely available, have significant abuse liability, and
are used increasingly for purposes. Opioid addiction affects the young and the old, the
wealthy and the poor, and the professional and the unemployed. Over the last few
decades there have been significant advances in treatment and understanding of opioid
dependence. It is increasingly accepted that opioid dependence is often a chronic,
relapsing disorder amenable to medical treatment and intervention. Table 20.7-1 lists
various opioids that are used therapeutically in the United States, with the exception of
heroin.
Table 20.7-1
Opioids
Opioid dependence is a cluster of physiological, behavioral, and cognitive symptoms, which together indicate repeated
and continuing use of opioid drugs, despite significant problems related to such use. Drug dependence, in general, has been
defined by the World Health Organization (WHO) as a syndrome in which the use of a drug or class of drugs takes on a
much higher priority for a given person than other behaviors that once had a higher value. These brief definitions each
have as their central features an emphasis on the drug-using behavior itself, its maladaptive nature, and how the choice to
engage in that behavior shifts and becomes constrained as a result of interaction with the drug over time.
Opioid abuse is a term used to designate a pattern of maladaptive use of an opioid drug leading to clinically significant
impairment or distress and occurring within a 12-month period, but one in which the symptoms have never met the
criteria for opioid dependence.
The opioid-induced disorders include such common phenomena as opioid use disorder,
opioid intoxication, opioid withdrawal, opioid-induced sleep disorder, and opioidinduced sexual dysfunction. Opioid intoxication delirium is occasionally seen in
hospitalized patients. Opioid-induced psychotic disorder, opioid-induced mood disorder,
and opioid-induced anxiety disorder, by contrast, are quite uncommon with μ-agonist
opioids, but have been seen with certain mixed agonist–antagonist opioids acting at
other receptors. The diagnosis of opioid-related disorder not elsewhere classified is used
for situations that do not meet the criteria for any of the other opioid-related disorders.
In addition to the morbidity and mortality associated directly with the opioid-related
disorders, the association between the transmission of the human immunodeficiency
virus (HIV) and intravenous opioid and opiate use is now recognized as a leading
national health concern. The words opiate and opioid come from the word opium, the
juice of the opium poppy, Papaver somniferum, which contains approximately 20 opium
alkaloids, including morphine.
Many synthetic opioids have been manufactured, including meperidine (Demerol),
methadone
(Dolophine),
pentazocine
(Talwin),
and
propoxyphene
(Darvon).
Methadone is the current gold standard in the treatment of opioid dependence. Opioid
antagonists have been synthesized to treat opioid overdose and opioid dependence. This
class of drugs includes naloxone (Narcan), naltrexone (ReVia), nalorphine,
levallorphan, and apomorphine. Compounds with mixed agonist and antagonist activity
at opioid receptors have been synthesized and include pentazocine, butorphanol
(Stadol), and buprenorphine (Buprenex). Studies have found buprenorphine to be an
effective treatment for opioid dependence.
EPIDEMIOLOGY
The use and dependence rates derived from national surveys do not accurately reflect
fluctuations in drug use among opioid-dependent and previously opioid-dependent
populations. When the supply of illicit heroin increases in purity or decreases in price,
use among that vulnerable population tends to increase, with subsequent increases in
adverse consequences (emergency room visits) and requests for treatment. The number
of current heroin users in the United States has been estimated to be between 600,000
and 800,000. The number of people estimated to have used heroin at any time in their
lives (lifetime users) is estimated at approximately 3 million.
In 2010, an estimated 140,000 persons had used heroin for the first time within the
past 12 months. The average age of first use among recent initiates was 21.3 years in
2010. Opioid use in the United States experienced a resurgence in the 1990s, with
emergency department visits related to heroin abuse doubling between 1990 and 1995.
This increase in heroin use was associated with an increase in heroin purity and a
decrease in its street price. In the late 1990s, heroin use increased among people who
were 18 to 25 years of age, and a brief upsurge was seen in the use of oxycodone
(OxyContin). Methods of administration other than injecting, such as smoking and
snorting, increased in popularity. In 2010, the number of new nonmedical users of
psychiatry of oxycodone was 598,000, with an average age at first use of 22.8 years.
Comparable data on past year oxycodone initiation are not available for prior years,
but calendar year estimates of oxycodone initiation show a steady increase in the
number of initiates from 1995, the year this drug was first available, through 2003. The
male-to-female ratio of persons with heroin dependence is about 3:1. Users of opioids
typically started to use substances in their teens and early 20s; currently, most persons
with opioid dependence are in their 30s and 40s. The tendency for dependence to remit
generally begins after age 40 years and has been called “maturing out.” Many persons,
however, have remained opioid dependent for 50 years or longer. In the United States,
persons tend to experience their first opioid-induced experience in their early teens or
even as young as 10 years of age. Early induction into the drug culture is likely in
communities in which substance abuse is rampant and in families in which the parents
are substance abusers. A heroin habit can cost a person hundreds of dollars a day; thus,
a person with opioid dependence needs to obtain money through criminal activities and
prostitution. The involvement of persons with opioid dependence in prostitution
accounts for much of the spread of HIV. The lifetime prevalence for heroin use is about 1
percent, with 0.2 percent having taken the drug during the prior year.
NEUROPHARMACOLOGY
The primary effects of the opioid drugs are mediated via the opioid receptors, which
were discovered in the first half of the 1970s (published in 1973). The μ-opioid receptors
are involved in the regulation and mediation of analgesia, respiratory depression,
constipation, and drug dependence; the κ-opioid receptors, with analgesia, diuresis, and
sedation; and the Δ-opioid receptors, with analgesia.
In 1975, the enkephalins, two endogenous pentapeptides with opioid-like actions,
were identified. This discovery led to the identification of three classes of endogenous
opioids within the brain, including the endorphins, the dynorphins, and the enkephalins.
The term “endorphin” (a contraction of “endogenous” and “morphine”) was coined by
Dr. Eric Simon, Professor of psychiatry at NYU School of Medicine, one of the scientists
who discovered the opioid receptors, to serve as a generic name for all molecules with
morphine-like activity found in the brain. Endorphins are involved in neural
transmission and pain suppression. They are released naturally in the body when a
person is physically hurt or severely stressed and are thought to account for the absence
of pain during acute injuries.
The endogenous opioids also have significant interactions with other neuronal
systems, such as the dopaminergic and noradrenergic neurotransmitter systems. Several
types of data indicate that the addictive rewarding properties of opioids are mediated
through activation of the ventral tegmental area dopaminergic neurons that project to
the cerebral cortex and the limbic system (Fig. 20.7-1).
FIGURE 20.7-1
Scheme illustrating opioid actions in the locus ceruleus (LC). Opioids acutely inhibit LC
neurons by increasing the conductance of a K+ channel (light cross-hatch) via coupling
with subtypes of Gi and/or Go and by decreasing an Na+-dependent inward current
(dark cross-hatch) via coupling with Gi/o and the consequent inhibition of adenylyl
cyclase. Reduced levels of cAMP decrease PKA and the phosphorylation of the
responsible channel or pump. Inhibition of the cyclic adenosine monophosphate (cAMP)
pathway also decreases phosphorylation of numerous other proteins and thereby affects
many additional processes in the neuron. For example, it reduces the phosphorylation
state of CREB, which may initiate some of the longer-term changes in LC function. Upper
bold arrows summarize effects of repeated morphine administration in the LC. Repeated
morphine administration increases levels of adenylyl cyclase, PKA, and several
phosphoproteins, including CREB. These changes contribute to the altered phenotype of
the drug-addicted state. For example, the intrinsic excitability of LC neurons is increased
via enhanced activity of the cAMP pathway and Na+-dependent inward current, which
contributes to the tolerance, dependence, and withdrawal exhibited by the these
neurons. This altered phenotypic state appears to be maintained, in part, by
upregulation of CREB expression. (From Nestler EJ. Molecular mechanisms underlying
opiate addiction: Implications for medications development. Semin Neurosci. 1997;9:84,
with permission.)
Heroin, the most commonly abused opioid, is more lipid soluble than morphine. This
allows it to cross the blood–brain barrier faster and have a more rapid and pleasurable
onset than morphine. Heroin was first introduced as a treatment for morphine
addiction, but heroin, in fact, is more dependence producing than morphine. Codeine,
which occurs naturally as about 0.5 percent of the opiate alkaloids in opium, is absorbed
easily through the gastrointestinal tract and is subsequently transformed into morphine
in the body. Results of at least one study using positron emission tomography (PET)
have suggested that one effect of all opioids is decreased cerebral blood flow in selected
brain regions in persons with opioid dependence. There is interesting evidence
indicating that the endorphins are involved in other addictions, such as alcoholism,
cocaine, and cannabinoid addiction. The opioid antagonist, naltrexone, has shown value
in mitigating alcohol addiction.
The discovery of this new endorphinergic neuromodulatory system has led to the
discovery of an endogenous cannabinoid system and has stimulated many outstanding
laboratories to do research toward improved pain management and prevention and
treatment of narcotic addiction.
Tolerance and Dependence
Tolerance to all actions of opioid drugs does not develop uniformly. Tolerance to some
actions of opioids can be so high that a 100-fold increase in dose is required to produce
the original effect. For example, terminally ill cancer patients may need 200 to 300 mg
a day of morphine, whereas a dose of 60 mg can easily be fatal to an opioid-naive
person. The symptoms of opioid withdrawal do not appear unless a person has been
using opioids for a long time or when cessation is particularly abrupt, as occurs
functionally when an opioid antagonist is given. The long-term use of opioids results in
changes in the number and sensitivity of opioid receptors, which mediate at least some
of the effects of tolerance and withdrawal. Although long-term use is associated with
increased sensitivity of the dopaminergic, cholinergic, and serotonergic neurons, the
effect of opioids on the noradrenergic neurons is probably the primary mediator of the
symptoms of opioid withdrawal. Short-term use of opioids apparently decreases the
activity of the noradrenergic neurons in the locus ceruleus; long-term use activates a
compensatory homeostatic mechanism within the neurons; and opioid withdrawal
results in rebound hyperactivity. This hypothesis also provides an explanation for why
clonidine (Catapres), an α2-adrenergic receptor agonist that decreases the release of
norepinephrine, is useful in the treatment of opioid withdrawal symptoms.
COMORBIDITY
About 90 percent of persons with opioid dependence have an additional psychiatric
disorder. The most common comorbid psychiatric diagnoses are major depressive
disorder, alcohol use disorders, antisocial personality disorder, and anxiety disorders.
About 15 percent of persons with opioid dependence attempt to commit suicide at least
once. The high prevalence of comorbidity with other psychiatric diagnoses (Table 20.72) highlights the need to develop a broad-based treatment program that also addresses
patients’ associated psychiatric disorders.
Table 20.7-2
Non–Substance-Related Psychiatric Disorders in Opioid Users
ETIOLOGY
Psychosocial Factors
Opioid dependence is not limited to low socioeconomic status (SES), although the
incidence of opioid dependence is greater in these groups than in higher SES groups.
Social factors associated with urban poverty probably contribute to opioid dependence.
About 50 percent of urban heroin users are children of single parents or divorced
parents and are from families in which at least one other member has a substancerelated disorder. Children from such settings are at high risk for opioid dependence,
especially if they also evidence behavioral problems in school or other signs of conduct
disorder.
Some consistent behavior patterns seem to be especially pronounced in adolescents
with opioid dependence. These patterns have been called the heroin behavior syndrome:
underlying depression, often of an agitated type and frequently accompanied by anxiety
symptoms; impulsiveness expressed by a passive-aggressive orientation; fear of failure;
use of heroin as an antianxiety agent to mask feelings of low self-esteem, hopelessness,
and aggression; limited coping strategies and low frustration tolerance, accompanied by
the need for immediate gratification; sensitivity to drug contingencies, with a keen
awareness of the relation between good feelings and the act of drug taking; feelings of
behavioral impotence counteracted by momentary control over the life situation by
means of substances; disturbances in social and interpersonal relationships with peers
maintained by mutual substance experiences.
Biological and Genetic Factors
Evidence now exists for common and drug-specific, genetically transmitted vulnerability
factors that increase the likelihood of developing drug dependence. Individuals who
abuse a substance from any category are more likely to abuse substances from other
categories. Monozygotic twins are more likely than dizygotic twins to be concordant for
opioid dependence. Multivariate modeling techniques have indicated that not only was
the genetic contribution high for heroin abuse in this group, but also a higher proportion
of the variance because of genetic factors was not shared with the common vulnerability
factor—that is, it was specific for opioids.
A person with an opioid-related disorder may have had genetically determined
hypoactivity of the opiate system. Researchers are investigating the possibility that such
hypoactivity may be caused by too few, or less-sensitive, opioid receptors, by release of
too little endogenous opioid, or by overly high concentrations of a hypothesized
endogenous opioid antagonist. A biological predisposition to an opioid-related disorder
may also be associated with abnormal functioning in either the dopaminergic or the
noradrenergic neurotransmitter system.
Psychodynamic Theory
In psychoanalytic literature, the behavior of persons addicted to narcotics has been
described in terms of libidinal fixation, with regression to pregenital, oral, or even more
archaic levels of psychosexual development. The need to explain the relation of drug
abuse, defense mechanisms, impulse control, affective disturbances, and adaptive
mechanisms led to the shift from psychosexual formulations to formulations emphasizing
ego psychology. Serious ego pathology, often thought to be associated with substance
abuse, is considered to indicate profound developmental disturbances. Problems of the
relation between the ego and affects emerge as a key area of difficulty.
DIAGNOSIS
Opioid Use Disorder
Opioid use disorder is a pattern of maladaptive use of an opioid drug, leading to
clinically significant impairment or distress and occurring within a 12-month period.
A 42-year-old executive in a public relations firm was referred for psychiatric
consultation by his surgeon, who discovered him sneaking large quantities of a
codeine-containing cough medicine into the hospital. The patient had been a heavy
cigarette smoker for 20 years and had a chronic, hacking cough. He had come into the
hospital for a hernia repair and found the pain from the incision unbearable when he
coughed.
An back operation 5 years previously had led his doctors to prescribe codeine to
help relieve the incisional pain at that time. Over the intervening 5 years, however,
the patient had continued to use codeine-containing tablets and had increased his
intake to 60–90 mg daily. He stated that he often “just took them by the handful—not
to feel good, you understand, just to get by.” He spent considerable time and effort
developing a circle of physicians and pharmacists to whom he would “make the
rounds” at least three times a week to obtain new supplies of pills. He had tried
several times to stop using codeine, but had failed. During this period he lost two jobs
because of lax work habits and was divorced by his wife of 11 years.
Opioid Intoxication
Opioid intoxication includes maladaptive behavioral changes and specific physical
symptoms of opioid use. In general, altered mood, psychomotor retardation, drowsiness,
slurred speech, and impaired memory and attention in the presence of other indicators
of recent opioid use strongly suggest a diagnosis of opioid intoxication.
Opioid Withdrawal
The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic
criteria for opioid withdrawal are listed in Table 20.7-3. The general rule about the
onset and duration of withdrawal symptoms is that substances with short durations of
action tend to produce short, intense withdrawal syndromes and substances with long
durations of action produce prolonged, but mild, withdrawal syndromes. An exception
to the rule, narcotic antagonist-precipitated withdrawal after long-acting opioid
dependence can be severe.
Table 20.7-3
DSM-5 Diagnostic Criteria for Opioid Withdrawal
An abstinence syndrome can be precipitated by administration of an opioid
antagonist. The symptoms can begin within seconds of such an intravenous injection
and peak in about 1 hour. Opioid craving rarely occurs in the context of analgesic
administration for pain from physical disorders or surgery. The full withdrawal
syndrome, including intense craving for opioids, usually occurs only secondary to abrupt
cessation of use in persons with opioid dependence.
Morphine and Heroin.
The morphine and heroin withdrawal syndrome begins 6
to 8 hours after the last dose, usually after a 1- to 2-week period of continuous use or
after the administration of a narcotic antagonist. The withdrawal syndrome reaches its
peak intensity during the second or third day and subsides during the next 7 to 10 days,
but some symptoms may persist for 6 months or longer.
Meperidine.
The withdrawal syndrome from meperidine begins quickly, reaches a
peak in 8 to 12 hours, and ends in 4 to 5 days.
Methadone.
Methadone withdrawal usually begins 1 to 3 days after the last dose
and ends in 10 to 14 days.
Symptoms.
Opioid withdrawal consists of severe muscle cramps and bone aches,
profuse diarrhea, abdominal cramps, rhinorrhea, lacrimation, piloerection or gooseflesh
(from which comes the term cold turkey for the abstinence syndrome), yawning, fever,
pupillary dilation, hypertension, tachycardia, and temperature dysregulation, including
hypothermia and hyperthermia. Persons with opioid dependence seldom die from opioid
withdrawal, unless they have a severe preexisting physical illness such as cardiac
disease. Residual symptoms—such as insomnia, bradycardia, temperature dysregulation,
and a craving for opioids—can persist for months after withdrawal. Associated features
of opioid withdrawal include restlessness, irritability, depression, tremor, weakness,
nausea, and vomiting. At any time during the abstinence syndrome, a single injection of
morphine or heroin eliminates all the symptoms.
Opioid Intoxication Delirium
Opioid intoxication delirium is most likely to happen when opioids are used in high
doses, are mixed with other psychoactive compounds, or are used by a person with
preexisting brain damage or a central nervous system (CNS) disorder (e.g., epilepsy).
Opioid-Induced Psychotic Disorder
Opioid-induced psychotic disorder can begin during opioid intoxication. Clinicians can
specify whether hallucinations or delusions are the predominant symptoms.
Opioid-Induced Mood Disorder
Opioid-induced mood disorder can begin during opioid intoxication. Opioid-induced
mood disorder symptoms can have a manic, depressed, or mixed nature, depending on a
person’s response to opioids. A person coming to psychiatric attention with opioidinduced mood disorder usually has mixed symptoms, combining irritability,
expansiveness, and depression.
Opioid-Induced Sleep Disorder and Opioid-Induced Sexual Dysfunction
Hypersomnia is likely to be more common with opioids than insomnia. The most
common sexual dysfunction is likely to be impotence.
Unspecified Opioid-Related Disorder
The DSM-5 includes diagnoses for other opioid-related disorders with symptoms of
delirium, abnormal mood, psychosis, abnormal sleep, and sexual dysfunction. Clinical
situations that do not fit into these categories exemplify appropriate cases for the use of
the DSM-5 diagnosis of unspecified opioid-related disorder.
CLINICAL FEATURES
Opioids can be taken orally, snorted intranasally, and injected intravenously or
subcutaneously (Fig. 20.7-2). Opioids are subjectively addictive because of the euphoric
high (the rush) that users experience, especially those who take the substances
intravenously. The associated symptoms include a feeling of warmth, heaviness of the
extremities, dry mouth, itchy face (especially the nose), and facial flushing. The initial
euphoria is followed by a period of sedation, known in street parlance as “nodding off.”
Opioid use can induce dysphoria, nausea, and vomiting in opioid-naive persons.
FIGURE 20.7-2
Skin popper. Circular depressed scars, often with underlying chronic abscesses, can
result from skin popping. (Courtesy of Michael Baden, M.D.)
The physical effects of opioids include respiratory depression, pupillary constriction,
smooth muscle contraction (including the ureters and the bile ducts), constipation, and
changes in blood pressure, heart rate, and body temperature. The respiratory depressant
effects are mediated at the level of the brainstem.
Adverse Effects
The most common and most serious adverse effect associated with the opioid-related
disorders is the potential transmission of hepatitis and HIV through the use of
contaminated needles by more than one person. Persons can experience idiosyncratic
allergic reactions to opioids, which result in anaphylactic shock, pulmonary edema, and
death if they do not receive prompt and adequate treatment. Another serious adverse
effect is an idiosyncratic drug interaction between meperidine and monoamine oxidase
inhibitors (MAOIs), which can produce gross autonomic instability, severe behavioral
agitation, coma, seizures, and death. Opioids and MAOIs should not be given together
for this reason.
Opioid Overdose
Death from an overdose of an opioid is usually attributable to respiratory arrest from
the respiratory depressant effect of the drug. The symptoms of overdose include marked
unresponsiveness, coma, slow respiration, hypothermia, hypotension, and bradycardia.
When presented with the clinical triad of coma, pinpoint pupils, and respiratory
depression, clinicians should consider opioid overdose as a primary diagnosis. They can
also inspect the patient’s body for needle tracks in the arms, legs, ankles, groin, and
even the dorsal vein of the penis.
MPTP-Induced Parkinsonism
In 1976, after ingesting an opioid contaminated with methyl-phenyltetrahydropyridine (MPTP), several persons developed
a syndrome of irreversible parkinsonism. The mechanism for the neurotoxic effect is as follows: MPTP is converted into 1methyl-4-phenylpyridinium (MPP+) by the enzyme monoamine oxidase and is then taken up by dopaminergic neurons.
Because MPP+ binds to melanin in substantia nigra neurons, MPP+ is concentrated in these neurons and eventually kills
the cells. PET studies of persons who ingested MPTP but remained asymptomatic have shown a decreased number of
dopamine-binding sites in the substantia nigra. This decrease reflects a loss in the number of dopaminergic neurons in that
region.
TREATMENT AND REHABILITATION
Overdose Treatment
The
first
task
in
overdose
treatment
is
to
ensure
an
adequate
airway.
Tracheopharyngeal secretions should be aspirated; an airway may be inserted. The
patient should be ventilated mechanically until naloxone, a specific opioid antagonist,
can be given. Naloxone is administered intravenously at a slow rate—initially about 0.8
mg per 70 kg of body weight. Signs of improvement (increased respiratory rate and
pupillary dilation) should occur promptly. In opioid-dependent patients, too much
naloxone may produce signs of withdrawal as well as reversal of overdosage. If no
response to the initial dosage occurs, naloxone administration may be repeated after
intervals of a few minutes. Previously, it was thought that if no response was observed
after 4 to 5 mg, the CNS depression was probably not caused solely by opioids. The
duration of action of naloxone is short compared with that of many opioids, such as
methadone and levomethadyl acetate, and repeated administration may be required to
prevent recurrence of opioid toxicity.
Medically Supervised Withdrawal and Detoxification
Opioid Agents for Treating Opioid Withdrawal
METHADONE. Methadone is a synthetic narcotic (an opioid) that substitutes for heroin
and can be taken orally. When given to addicts to replace their usual substance of
abuse, the drug suppresses withdrawal symptoms. A daily dose of 20 to 80 mg suffices to
stabilize a patient, although daily doses of up to 120 mg have been used. The duration
of action for methadone exceeds 24 hours; thus, once-daily dosing is adequate.
Methadone maintenance is continued until the patient can be withdrawn from
methadone, which itself causes dependence. An abstinence syndrome occurs with
methadone withdrawal, but patients are detoxified from methadone more easily than
from heroin. Clonidine (0.1 to 0.3 mg three to four times a day) is usually given during
the detoxification period.
Methadone maintenance has several advantages. First, it frees persons with opioid
dependence from using injectable heroin and, thus, reduces the chance of spreading HIV
through contaminated needles. Second, methadone produces minimal euphoria and
rarely causes drowsiness or depression when taken for a long time. Third, methadone
allows patients to engage in gainful employment instead of criminal activity. The major
disadvantage of methadone use is that patients remain dependent on a narcotic.
Other Opioid Substitutes
LEVOMETHADYL (LAAM). LAAM is an opioid agonist that suppresses opioid withdrawal. It
is no longer used, however, because some patients developed prolonged QT intervals
associated with potentially fatal arrhythmias (torsades de pointes).
BUPRENORPHINE. As with methadone and LAAM, buprenorphine is an opioid agonist
approved for opioid dependence in 2002. It can be dispensed on an outpatient basis, but
prescribing physicians must demonstrate that they have received special training in its
use. Buprenorphine in a daily dose of 8 to 10 mg appears to reduce heroin use.
Buprenorphine also is effective in thrice-weekly dosing because of its slow dissociation
from opioid receptors. After repeated administration, it attenuates or blocks the
subjective effects of parenterally administered opioids such as heroin or morphine. A
mild opioid withdrawal syndrome occurs if the drug is abruptly discontinued after
chronic administrations.
Opioid Antagonists.
Opioid antagonists block or antagonize the effects of opioids.
Unlike methadone, they do not exert narcotic effects and do not cause dependence.
Opioid antagonists include naloxone, which is used in the treatment of opioid overdose
because it reverses the effects of narcotics, and naltrexone, the longest-acting (72 hours)
antagonist. The theory for using an antagonist for opioid-related disorders is that
blocking opioid agonist effects, particularly euphoria, discourages persons with opioid
dependence from substance-seeking behavior and, thus, deconditions this behavior. The
major weakness of the antagonist treatment model is the lack of any mechanism that
compels a person to continue to take the antagonist.
Pregnant Women with Opioid Dependence
Neonatal addiction is a significant problem. About three fourths of all infants born to
addicted mothers experience the withdrawal syndrome.
Neonatal Withdrawal.
Although opioid withdrawal rarely is fatal for the
otherwise healthy adult, it is hazardous to the fetus and can lead to miscarriage or fetal
death. Maintaining a pregnant woman with opioid dependence on a low dose of
methadone (10 to 40 mg daily) may be the least hazardous course to follow. At this
dose, neonatal withdrawal is usually mild and can be managed with low doses of
paregoric. If pregnancy begins while a woman is taking high doses of methadone, the
dosage should be reduced slowly (e.g., 1 mg every 3 days), and fetal movements should
be monitored. If withdrawal is necessary or desired, it is least hazardous during the
second trimester.
Fetal AIDS Transmission.
Acquired immune deficiency syndrome (AIDS) is the
other major risk to the fetus of a woman with opioid dependence. Pregnant women can
pass HIV, the causative agent of AIDS, to the fetus through the placental circulation. An
HIV-infected mother can also pass HIV to the infant through breast-feeding. The use of
zidovudine (Retrovir) alone or in combination with other anti-HIV medication in
infected women can decrease the incidence of HIV in newborns.
Psychotherapy
The entire range of psychotherapeutic modalities is appropriate for treating opioidrelated disorders. Individual psychotherapy, behavioral therapy, cognitive-behavioral
therapy, family therapy, support groups (e.g., Narcotics Anonymous [NA]), and social
skills training may all prove effective for specific patients. Social skills training should
be particularly emphasized for patients with few social skills. Family therapy is usually
indicated when the patient lives with family members.
Therapeutic Communities
Therapeutic communities are residences in which all members have a substance abuse
problem. Abstinence is the rule; to be admitted to such a community, a person must
show a high level of motivation. The goals are to effect a complete change of lifestyle,
including abstinence from substances; to develop personal honesty, responsibility, and
useful social skills; and to eliminate antisocial attitudes and criminal behavior.
The staff members of most therapeutic communities are persons with former substance
dependence who often put prospective candidates through a rigorous screening process
to test their motivation. Self-help through the use of confrontational groups and
isolation from the outside world and from friends associated with the drug life are
emphasized. The prototypical community for persons with substance dependence is
Phoenix House, where the residents live for long periods (usually 12 to 18 months) while
receiving treatment. They are allowed to return to their old environments only when
they have demonstrated their ability to handle increased responsibility within the
therapeutic community. Therapeutic communities can be effective but require large
staffs and extensive facilities. Moreover, dropout rates are high; up to 75 percent of
those who enter therapeutic communities leave within the first month.
Education and Needle Exchange.
Although the essential treatment of opioid
use disorders is encouraging persons to abstain from opioids, education about the
transmission of HIV must receive equal attention. Persons with opioid dependence who
use intravenous or subcutaneous routes of administration must be taught available safe-
sex practices. Free needle-exchange programs are often subject to intense political and
societal pressures but, where allowed, should be made available to persons with opioid
dependence. Several studies have indicated that unsafe needle sharing is common when
it is difficult to obtain enough clean needles and is also common in persons with legal
difficulties, severe substance problems, and psychiatric symptoms. These are just the
persons most likely to be involved in transmitting HIV.
Narcotic Anonymous
Narcotics Anonymous is a self-help group of abstinent drug addicts modeled on the 12step principles of Alcoholics Anonymous (AA). Such groups now exist in most large cities
and can provide useful group support. The outcome for patients treated in 12-step
programs is generally good, but the anonymity that is at the core of the 12-step model
has made detailed evaluation of its efficacy in treating opioid dependence difficult.
REFERENCES
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08 - 20.8 Sedative , Hypnotic , or Anxiolytic Rela
20.8 Sedative-, Hypnotic-, or Anxiolytic-Related Disorders
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20.8 Sedative-, Hypnotic-, or Anxiolytic-Related Disorders
The drugs discussed in this section are referred to as anxiolytic or sedative–hypnotic drugs.
Their sedative or calming effects are on a continuum with their hypnotic or sleepinducing effects. In addition to their psychiatric indications, these drugs are also used as
antiepileptics, muscle relaxants, anesthetics, and anesthetic adjuvants. Alcohol and all
drugs of this class are cross-tolerant, and their effects are additive. Physical and
psychological dependence develops to these drugs, and all are associated with
withdrawal symptoms. In the practice of psychiatry and addiction medicine, the drug
class that is most important clinically is the benzodiazepines.
The three major groups of drugs associated with this class of substance-related
disorders are benzodiazepines, barbiturates, and barbiturate-like substances. Each group
is discussed below.
BENZODIAZEPINES
Many benzodiazepines, differing primarily in their half-lives, are available in the United
States. Examples of benzodiazepines are diazepam, flurazepam (Dalmane), oxazepam
(Serax), and chlordiazepoxide (Librium). Benzodiazepines are used primarily as
anxiolytics, hypnotics, antiepileptics, and anesthetics, as well as for alcohol withdrawal.
After their introduction in the United States in the 1960s, benzodiazepines rapidly
became the most prescribed drugs; about 15 percent of all persons in the United States
have had a benzodiazepine prescribed by a physician. Increasing awareness of the risks
for dependence on benzodiazepines and increased regulatory requirements, however,
have decreased the number of benzodiazepine prescriptions. The Drug Enforcement
Agency (DEA) classifies all benzodiazepines as Schedule IV controlled substances.
Flunitrazepam (Rohypnol), a benzodiazepine used in Mexico, South America, and
Europe but not available in the United States, has become a drug of abuse. When taken
with alcohol, it has been associated with promiscuous sexual behavior and rape. It is
illegal to bring flunitrazepam into the United States. Although misused in the United
States, it remains a standard anxiolytic in many countries.
Non-benzodiazepine sedatives such as zolpidem (Ambien) zaleplon (Sonata), and
eszopiclone (Lunesta)—the so called Z drugs—have clinical effects similar to the
benzodiazepines and are also subject to misuse and dependence.
BARBITURATES
Before the introduction of benzodiazepines, barbiturates were frequently prescribed, but
because of their high abuse potential, their use is much rarer today. Secobarbital
(popularly known as “reds,” “red devils,” “seggies,” and “downers”), pentobarbital
(Nembutal) (known as “yellow jackets,” “yellows,” and “nembies”), and a secobarbital–
amobarbital combination (known as “reds and blues,” “rainbows,” “double-trouble,” and
“tooies”) are easily available on the street from drug dealers. Pentobarbital,
secobarbital, and amobarbital (Amytal) are now under the same federal legal controls
as morphine.
The first barbiturate, barbital (Veronal), was introduced in the United States in 1903.
Barbital and phenobarbital (Solfoton, Luminal), which was introduced shortly
thereafter, are long-acting drugs with half-lives of 12 to 24 hours. Amobarbital is an
intermediate-acting barbiturate with a half-life of 6 to 12 hours. Pentobarbital and
secobarbital are short-acting barbiturates with half-lives of 3 to 6 hours. Although
barbiturates are useful and effective sedatives, they are highly lethal with only ten times
the normal dose producing coma and death.
BARBITURATE-LIKE SUBSTANCES
The most commonly abused barbiturate-like substance is methaqualone, which is no
longer manufactured in the United States. It is often used by young persons who believe
that the substance heightens the pleasure of sexual activity. Abusers of methaqualone
commonly take one or two standard tablets (usually 300 mg per tablet) to obtain the
desired effects. The street names for methaqualone include “mandrakes” (from the
United Kingdom preparation Mandrax) and “soapers” (from the brand name Sopor).
“Luding out” (from the brand name Quaalude) means getting high on methaqualone,
which is often combined with excessive alcohol intake.
Other barbiturate-like substances include meprobamate (Equanil), a carbamate
derivative that has weak efficacy as an antianxiety agent but has muscle-relaxant effects
and is used for that purpose; chloral hydrate, a hypnotic that is highly toxic to the
gastrointestinal (GI) system and, when combined with alcohol, is known as a “mickey
finn”; and ethchlorvynol, a rapidly acting sedative agent with anticonvulsant and
muscle-relaxant properties. All are subject to abuse.
EPIDEMIOLOGY
About 6 percent of individuals have used either sedatives or tranquilizers illicitly,
including 0.3 percent who reported illicit use of sedatives in the prior year and 0.1
percent who reported use of sedatives in the prior month. The age group with the
highest lifetime prevalence of sedative (3 percent) or tranquilizer (6 percent) use was 26
to 34 years of age, and those aged 18 to 25 were most likely to have used sedatives or
tranquilizers in the prior year. About one fourth to one third of all substance-related
emergency room visits involve substances of this class. The patients have a female-tomale ratio of 3:1 and a white-to-black ratio of 2:1. Some persons use benzodiazepines
alone, but persons who use cocaine often use benzodiazepines to reduce withdrawal
symptoms, and opioid abusers use them to enhance the euphoric effects of opioids.
Because they are easily obtained, benzodiazepines are also used by abusers of
stimulants, hallucinogens, and phencyclidine (PCP) to help reduce the anxiety that can
be caused by those substances.
Whereas barbiturate abuse is common among mature adults who have long histories
of abuse of these substances, benzodiazepines are abused by a younger age group,
usually those under 40 years of age. This group may have a slight male predominance
and has a white-to-black ratio of about 2:1. Benzodiazepines are probably not abused as
frequently as other substances for the purpose of getting “high,” or inducing a euphoric
feeling. Rather, they are used when a person wishes to experience a general relaxed
feeling.
NEUROPHARMACOLOGY
The benzodiazepines, barbiturates, and barbiturate-like substances all have their
primary effects on the γ-aminobutyric acid (GABA) type A (GABAA) receptor complex,
which contains a chloride ion channel, a binding site for GABA, and a well-defined
binding site for benzodiazepines. The barbiturates and barbiturate-like substances are
also believed to bind somewhere on the GABAA receptor complex. When a
benzodiazepine, barbiturate, or barbiturate-like substance does bind to the complex, the
effect is to increase the affinity of the receptor for its endogenous neurotransmitter,
GABA, and to increase the flow of chloride ions through the channel into the neuron.
The influx of negatively charged chloride ions into the neuron is inhibitory, and
hyperpolarizes the neuron relative to the extracellular space.
Although all the substances in this class induce tolerance and physical dependence, the
mechanisms behind these effects are best understood for the benzodiazepines. After
long-term benzodiazepine use, the receptor effects caused by the agonist are attenuated.
Specifically, GABA stimulation of the GABAA receptors results in less chloride influx than
was caused by GABA stimulation before the benzodiazepine administration. This
downregulation of receptor response is not caused by a decrease in receptor number or
by decreased affinity of the receptor for GABA. The basis for the downregulation seems
to be in the coupling between the GABA binding site and the activation of the chloride
ion channel. This decreased efficiency in coupling may be regulated within the GABAA
receptor complex itself or by other neuronal mechanisms.
DIAGNOSIS
Sedative, Hypnotic, or Anxiolytic Use Disorder
Sedative, hypnotic, or anxiolytic use disorder is diagnosed according to the general
criteria in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) for substance use disorder (see page 621).
Sedative, Hypnotic, or Anxiolytic Intoxication
The intoxication syndromes induced by all these drugs are similar, and include
incoordination, dysarthria, nystagmus, impaired memory, gait disturbance, and in
severe cases stupor, coma, or death. The diagnosis of intoxication by one of this class of
substances is best confirmed by obtaining a blood sample for substance screening.
Benzodiazepines.
Benzodiazepine intoxication can be associated with behavioral
disinhibition, potentially resulting in hostile or aggressive behavior in some persons.
The effect is perhaps most common when benzodiazepines are taken in combination
with alcohol. Benzodiazepine intoxication is associated with less euphoria than is
intoxication by other drugs in this class. This characteristic is the basis for the lower
abuse and dependence potential of benzodiazepines than of barbiturates.
Barbiturates and Barbiturate-like Substances.
When barbiturates and
barbiturate-like substances are taken in relatively low doses, the clinical syndrome of
intoxication is indistinguishable from that associated with alcohol intoxication. The
symptoms include sluggishness, incoordination, difficulty thinking, poor memory, slow
speech and comprehension, faulty judgment, disinhibited sexual aggressive impulses,
narrowed range of attention, emotional lability, and exaggerated basic personality
traits. The sluggishness usually resolves after a few hours, but depending primarily on
the half-life of the abused substance, impaired judgment, distorted mood, and impaired
motor skills may remain for 12 to 24 hours. Other potential symptoms are hostility,
argumentativeness, moroseness, and, occasionally, paranoid and suicidal ideation. The
neurological effects include nystagmus, diplopia, strabismus, ataxic gait, positive
Romberg’s sign, hypotonia, and decreased superficial reflexes.
Sedative, Hypnotic, or Anxiolytic Withdrawal
Benzodiazepines.
The severity of the withdrawal syndrome associated with the
benzodiazepines varies significantly depending on the average dose and the duration of
use, but a mild withdrawal syndrome can follow even short-term use of relatively low
doses of benzodiazepines. A significant withdrawal syndrome is likely to occur at
cessation of dosages in the range of 40 mg a day for diazepam, for example, although
10 to 20 mg a day, taken for a month, can also result in a withdrawal syndrome when
drug administration is stopped. The onset of withdrawal symptoms usually occurs 2 to 3
days after the cessation of use, but with long-acting drugs, such as diazepam, the latency
before onset can be 5 or 6 days. The symptoms include anxiety, dysphoria, intolerance
for bright lights and loud noises, nausea, sweating, muscle twitching, and sometimes
seizures (generally at dosages of 50 mg a day or more of diazepam). Table 20.8-1 lists
the signs and symptoms of benzodiazepine withdrawal.
Table 20.8-1
Signs and Symptoms of the Benzodiazepine Discontinuation Syndrome
Barbiturates and Barbiturate-like Substances.
The withdrawal syndrome for
barbiturate and barbiturate-like substances ranges from mild symptoms (e.g., anxiety,
weakness, sweating, and insomnia) to severe symptoms (e.g., seizures, delirium,
cardiovascular collapse, and death). Persons who have been abusing phenobarbital in
the range of 400 mg a day may experience mild withdrawal symptoms; those who have
been abusing the substance in the range of 800 mg a day can experience orthostatic
hypotension, weakness, tremor, and severe anxiety. About 75 percent of these persons
have withdrawal-related seizures. Users of dosages higher than 800 mg a day may
experience anorexia, delirium, hallucinations, and repeated seizures.
Most symptoms appear in the first 3 days of abstinence, and seizures generally occur
on the second or third day, when the symptoms are worst. If seizures do occur, they
always precede the development of delirium. The symptoms rarely occur more than a
week after stopping the substance. A psychotic disorder, if it develops, starts on the
third to eighth day. The various associated symptoms generally run their course within 2
to 3 days, but can last as long as 2 weeks. The first episode of the syndrome usually
occurs after 5 to 15 years of heavy substance use.
Other Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders
Delirium.
Delirium that is indistinguishable from delirium tremens associated with
alcohol withdrawal is seen more commonly with barbiturate withdrawal than with
benzodiazepine withdrawal. Delirium associated with intoxication can be seen with
either barbiturates or benzodiazepines if the dosages are sufficiently high.
Persisting Dementia.
The existence of the sedative/hypnotic-induced persisting
dementia is controversial, because uncertainty exists whether a persisting dementia is
caused by the substance use itself or by associated features of the substance use.
Persisting Amnestic Disorder.
Amnestic disorders associated with sedatives and
hypnotics may be underdiagnosed. One exception is the increased number of reports of
amnestic episodes associated with short-term use of benzodiazepines with short half-lives
(e.g., triazolam [Halcion]).
Psychotic Disorders.
The psychotic symptoms of barbiturate withdrawal can be
indistinguishable from those of alcohol-associated delirium tremens. Agitation,
delusions, and hallucinations are usually visual, but sometimes tactile or auditory
features develop after about 1 week of abstinence. Psychotic symptoms associated with
intoxication or withdrawal are more common with barbiturates than with
benzodiazepines. They are diagnosed in DSM-5 as sedative, hypnotic, or anxiolytic
withdrawal with perceptual disturbances when reality testing is intact (the individual is
aware the drug is causing the psychotic symptoms). If reality testing is not intact (the
individual believes the hallucinations are real), a diagnosis of substance/medicationinduced psychotic disorder is more appropriate. Clinicians can further specify whether
delusions or hallucinations are the predominant symptoms, including the type (e.g.
auditory, visual, or tactile).
Other Disorders.
Sedative and hypnotic use has also been associated with mood
disorders, anxiety disorders, sleep disorders, and sexual dysfunctions.
Unspecified Sedative-, Hypnotic-, or Anxiolytic-Related Disorder.
When
none of the previously discussed diagnostic categories is appropriate for a person with
sedative-, hypnotic-, or anxiolytic-related disorder, and he or she does not meet the
diagnostic criteria for any general substance-related disorder (see page 621), the
appropriate diagnosis is unspecified sedative-, hypnotic-, or anxiolytic-related disorder.
CLINICAL FEATURES
Patterns of Abuse
Oral Use.
Sedatives and hypnotics can all be taken orally, either occasionally to
achieve a time-limited specific effect or regularly to obtain a constant, usually mild,
intoxication state. The occasional use pattern is associated with young persons who take
the substance to achieve specific effects—relaxation for an evening, intensification of
sexual activities, and a short-lived period of mild euphoria. The user’s personality and
expectations about the substance’s effects and the setting in which the substance is taken
also affect the substance-induced experience. The regular use pattern is associated with
middle-aged, middle-class persons who usually obtain the substance from a family
physician as a prescription for insomnia or anxiety. Abusers of this type may have
prescriptions from several physicians, and the pattern of abuse may go undetected until
obvious signs of abuse or dependence are noticed by the person’s family, coworkers, or
physicians.
Intravenous Use.
A severe form of abuse involves the intravenous use of this class
of substances. The users are mainly young adults who are intimately involved with
illegal substances. Intravenous barbiturate use is associated with a pleasant, warm,
drowsy feeling, and users may be inclined to use barbiturates more than opioids because
barbiturates are less costly. The physical dangers of injection include transmission of the
human immunodeficiency virus (HIV), cellulitis, vascular complications from accidental
injection into an artery, infections, and allergic reactions to contaminants. Intravenous
use is associated with rapid and profound tolerance and dependence and a severe
withdrawal syndrome.
Overdose
Benzodiazepines.
In contrast to the barbiturates and the barbiturate-like
substances, the benzodiazepines have a large margin of safety when taken in overdoses,
a feature that has contributed significantly to their rapid acceptance. The ratio of lethal
dose to effective dose is about 200 to 1 or higher, because of the minimal degree of
respiratory depression associated with the benzodiazepines. A list of equivalent
therapeutic doses of benzodiazepines is given in Table 20.8-2. Even when grossly
excessive amounts (more than 2 g) are taken in suicide attempts, the symptoms include
only drowsiness, lethargy, ataxia, some confusion, and mild depression of the user’s
vital signs. A much more serious condition prevails when benzodiazepines are taken in
overdose in combination with other sedative-hypnotic substances, such as alcohol. In
such cases, small doses of benzodiazepines can cause death. The availability of
flumazenil (Romazicon), a specific benzodiazepine antagonist, has reduced the lethality
of the benzodiazepines. Flumazenil can be used in emergency rooms to reverse the
effects of the benzodiazepines.
Table 20.8-2
Approximate Therapeutic Equivalent Doses of Benzodiazepines
Barbiturates.
Barbiturates are lethal when taken in overdose because they induce
respiratory depression. In addition to intentional suicide attempts, accidental or
unintentional overdoses are common. Barbiturates in home medicine cabinets are a
common cause of fatal drug overdoses in children. As with benzodiazepines, the lethal
effects of the barbiturates are additive to those of other sedatives or hypnotics, including
alcohol and benzodiazepines. Barbiturate overdose is characterized by the induction of
coma, respiratory arrest, cardiovascular failure, and death.
The lethal dose varies with the route of administration and the degree of tolerance for
the substance after a history of long-term abuse. For the most commonly abused
barbiturates, the ratio of lethal dose to effective dose ranges between 3:1 and 30:1.
Dependent users often take an average daily dose of 1.5 g of a short-acting barbiturate,
and some have been reported to take as much as 2.5 g a day for months.
The lethal dose is not much greater for the long-term abuser than for the neophyte.
Tolerance develops quickly, to the point at which withdrawal in a hospital becomes
necessary to prevent accidental death from overdose.
Barbiturate-like Substances.
The barbiturate-like substances vary in their
lethality and are usually intermediate between the relative safety of the
benzodiazepines and the high lethality of the barbiturates. An overdose of
methaqualone, for example, can result in restlessness, delirium, hypertonia, muscle
spasms, convulsions, and, in very high doses, death. Unlike barbiturates, methaqualone
rarely causes severe cardiovascular or respiratory depression, and most fatalities result
from combining methaqualone with alcohol.
TREATMENT AND REHABILITATION
Withdrawal
Benzodiazepines.
Because some benzodiazepines are eliminated from the body
slowly, symptoms of withdrawal can continue to develop for several weeks. To prevent
seizures and other withdrawal symptoms, clinicians should gradually reduce the dosage.
Several reports indicate that carbamazepine (Tegretol) may be useful in the treatment
of benzodiazepine withdrawal. Table 20.8-3 lists guidelines for treating benzodiazepine
withdrawal.
Table 20.8-3
Guidelines for Treatment of Benzodiazepine Withdrawal
Barbiturates.
To avoid sudden death during barbiturate withdrawal, clinicians
must follow conservative clinical guidelines. Clinicians should not give barbiturates to a
comatose or grossly intoxicated patient. A clinician should attempt to determine a
patient’s usual daily dose of barbiturates and then verify the dosage clinically. For
example, a clinician can give a test dose of 200 mg of pentobarbital every hour until a
mild intoxication occurs but withdrawal symptoms are absent (Table 20.8-4). The
clinician can then taper the total daily dose at a rate of about 10 percent of the total
daily dose. Once the correct dosage is determined, a long-acting barbiturate can be used
for the detoxification period. During this process, the patient may begin to experience
withdrawal symptoms, in which case the clinician should halve the daily decrement.
Table 20.8-4
Pentobarbital Test Dose Procedure for Barbiturate Withdrawal
In the withdrawal procedure, phenobarbital can be substituted for the more commonly
abused short-acting barbiturates. The effects of phenobarbital last longer, and because
barbiturate blood levels fluctuate less, phenobarbital does not cause observable toxic
signs or a serious overdose. An adequate dose is 30 mg of phenobarbital for every 100
mg of the short-acting substance. The user should be maintained for at least 2 days at
that level before the dose is reduced further. The regimen is analogous to the
substitution of methadone for heroin.
After withdrawal is complete, the patient must overcome the desire to start taking the
substance again. Although substitution of nonbarbiturate sedatives or hypnotics for
barbiturates has been suggested as a preventive therapeutic measure, this often results
in replacing one substance dependence with another. If a user is to remain substance
free, follow-up treatment, usually with psychiatric help and community support, is vital.
Otherwise, a patient will almost certainly return to barbiturates or a substance with
similar hazards.
Overdose
The treatment of overdose of this class of substances involves gastric lavage, activated
charcoal, and careful monitoring of vital signs and central nervous system (CNS)
activity. Patients who overdose and come to medical attention while awake should be
kept from slipping into unconsciousness. Vomiting should be induced, and activated
charcoal should be administered to delay gastric absorption. If a patient is comatose, the
clinician must establish an intravenous fluid line, monitor the patient’s vital signs, insert
an endotracheal tube to maintain a patent airway, and provide mechanical ventilation,
if necessary. Hospitalization of a comatose patient in an intensive care unit is usually
required during the early stages of recovery from such overdoses.
EXPERT OPINION
The International Study of Expert Judgment on Therapeutic Use of Benzodiazepines and
Other Psychotherapeutic Medications was designed to gather systematic data on the
opinions of leading clinicians concerning the benefits and risks of benzodiazepines and
alternative treatments of anxiety. This survey study addressed the relative risks of
benzodiazepines compared with other agents and comparative risks within the class.
The expert panel assessed risk based on a drug’s potential to produce tolerance, rebound
symptoms, a withdrawal syndrome, and ease of discontinuation.
Two thirds of the expert panel reported that long-term use of benzodiazepines for the
treatment of anxiety disorders does not pose a high risk of dependence and abuse.
Although agreement was that the pharmacological properties of the medication may be
the most important contributor to development of withdrawal symptoms, no consensus
existed on whether benzodiazepines with shorter and longer half-lives have similar
dependence potential. A clear consensus was that the differences in withdrawal
symptoms are clinically negligible with gradual dose tapering. Because differences in
abuse liability among the various benzodiazepines have not been demonstrated in
humans, and because the benefits of benzodiazepine treatment clearly outweigh the
risks, most physicians on the expert panel opposed increased restrictions on
benzodiazepine prescribing.
Despite the expert opinion stated earlier, state and federal agencies have attempted to restrict the distribution of
benzodiazepines by requiring special reporting forms. For example, in New York State, through the use of a newly enacted
prescription monitoring program (PMP) called I-STOP, effective since August 27, 2013, doctors cannot write a
prescription for a benzodiazepine unless they first search a computerized database that contains the names of all persons
in the state who were ever prescribed benzodiazepines and other controlled substances. Governments have taken these and
other such measures in an attempt to stem the tide of abuse. However most abuse results from the illicit manufacture,
sale, and diversion of substances, particularly to cocaine and opioid addicts, not from physicians’ prescriptions or
legitimate pharmaceutical companies. These programs do not stem the tide of illegal use of valuable medications and
interfere in the practice of medicine and in the confidential relationship between doctor and patient.
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20.9 Stimulant-Related Disorders
AMPHETAMINES
Amphetamines and amphetamine-like drugs are among the most widely used illicit
substances, second only to cannabis, in the United States, Asia, Great Britain, Australia,
and several other Western European countries. Methamphetamine, a congener of
amphetamine, has become even more popular in recent years.
The racemic amphetamine sulfate (Benzedrine) was first synthesized in 1887, and it was introduced to clinical practice
in 1932 as an over-the-counter inhaler for the treatment of nasal congestion and asthma. In 1937, amphetamine sulfate
tablets were introduced for the treatment of narcolepsy, postencephalitic parkinsonism, depression, and lethargy. In the
1970s, a variety of social and regulatory factors began to curb widespread amphetamine distribution. The current U.S.
Food and Drug Administration (FDA)–approved indications for amphetamine are limited to attention-deficit/hyperactivity
disorder (ADHD) and narcolepsy; however, amphetamines are also used in the treatment of obesity, depression,
dysthymia, chronic fatigue syndrome, acquired immunodeficiency syndrome (AIDS), dementia, multiple sclerosis,
fibromyalgia, and neurasthenia.
Preparations
The major amphetamines currently available and used in the United States are
dextroamphetamine
(Dexedrine),
methamphetamine
(Desoxyn),
a
mixed
dextroamphetamine-amphetamine salt (Adderall), and the amphetamine-like compound
methylphenidate (Ritalin). These drugs go by such street names as ice, crystal, crystal
meth, and speed. As a general class, the amphetamines are referred to as analeptics,
sympathomimetics, stimulants, and psychostimulants. The typical amphetamines are
used to increase performance and to induce a euphoric feeling, for example, by students
studying for examinations, by long-distance truck drivers on trips, by business people
with important deadlines, by athletes in competition, and by soldiers during wartime.
Although not as addictive as cocaine, amphetamines are nonetheless addictive drugs.
Other
amphetamine-like
substances
are
ephedrine,
pseudoephedrine,
and
phenylpropanolamine (PPA). These drugs, PPA in particular, can dangerously
exacerbate hypertension, precipitate a toxic psychosis, cause intestinal infarction, or
result in death. The safety margin for PPA is particularly narrow, and three to four
times the normal dose can result in life-threatening hypertension. In 2005, medications
containing PPA were recalled by the FDA, and in 2006, the FDA prohibited the sale of
over-the-counter medications containing ephedrine and regulated the sale of over-thecounter medications containing pseudoephedrine, which was being used illegally to
make methamphetamine.
Amphetamine-type drugs with abuse potential also include phendimetrazine
(Preludin), which is included in Schedule II of the Controlled Substance Act (CSA), and
diethylpropion (Tenuate), benzphetamine (Didrex), and phentermine (Ionamin), which
are included in Schedules III or IV of the CSA. It is presumed that all of these drugs are
capable of producing all of the listed amphetamine-induced disorders. Modafinil
(Provigil), used in the treatment of narcolepsy, also has stimulant and euphorigenic
effects in humans, but its toxicity and likelihood of producing amphetamine-induced
disorders are unknown.
Methamphetamine is a potent form of amphetamine that abusers of the substance
inhale, smoke, or inject intravenously. Its psychological effects last for hours and are
described as particularly powerful. Unlike cocaine (see discussion later in this section),
which must be imported, methamphetamine is a synthetic drug that can be
manufactured domestically in illicit laboratories.
Other agents called substituted or designer amphetamines are discussed separately later
in this section.
Epidemiology
Amphetamine-type stimulant abuse represents major public health and law enforcement
problems in the United States and abroad, primarily due to the consumption of
methamphetamine. According to the Community Epidemiology Work Group,
methamphetamine abuse occurs at epidemic levels in Hawaii, on the West Coast, and in
some Southern states, and continues to spread eastward. Nationally, treatment
admission rates for methamphetamine dependence more than doubled between 1995
and 2012, and in the western United States, treatment admission rates for
methamphetamine dependence are higher than those of either cocaine or heroin.
According to the National Association of Counties, nearly half (48 percent) of 500
county law enforcement agencies in the United States name methamphetamine as the
primary drug problem, more than cocaine (22 percent), marijuana (22 percent), and
heroin (2 percent) combined. Similarly, almost 40 percent of state and local law
enforcement agencies identify methamphetamine as their greatest drug threat, second
only to cocaine, a higher percentage than any other drug.
On a global basis, use of amphetamine-type stimulants, including methamphetamine,
is also a major concern, ranking as the second most widely used substance, following
marijuana, according to a report from the United Nations Office on Drugs and Crime.
According to the 2010 National Survey on Drug Use and Health (NSDUH), 353,000
persons 12 years or older were current users of methamphetamine (0.1 percent).
Neuropharmacology
All the amphetamines are rapidly absorbed orally and have a rapid onset of action,
usually within 1 hour when taken orally. The classic amphetamines are also taken
intravenously and have an almost immediate effect by this route. Nonprescribed
amphetamines and designer amphetamines are also inhaled (“snorting”). Tolerance
develops with both classic and designer amphetamines, although amphetamine users
often overcome the tolerance by taking more of the drug. Amphetamine is less addictive
than cocaine, as evidenced by experiments on rats in which not all animals
spontaneously self-administered low doses of amphetamine.
The classic amphetamines (i.e., dextroamphetamine, methamphetamine, and
methylphenidate)
produce
their
primary
effects
by
causing
the
release
of
catecholamines, particularly dopamine, from presynaptic terminals. The effects are
particularly potent for the dopaminergic neurons projecting from the ventral tegmental
area to the cerebral cortex and the limbic areas. This pathway has been termed the
reward circuit pathway, and its activation is probably the major addicting mechanism for
the amphetamines. The designer amphetamines cause the release of catecholamines
(dopamine and norepinephrine) and of serotonin, the neurotransmitter implicated as
the major neurochemical pathway for hallucinogens. Therefore, the clinical effects of
designer amphetamines are a blend of the effects of classic amphetamines and those of
hallucinogens.
COCAINE
Cocaine has been used in its raw form for more than 15 centuries. In the United States,
cycles of widespread stimulant misuse and associated problems have occurred for more
than 100 years. Cocaine and cocaine use disorders became a major public health issue in
the 1980s when an epidemic of use spread throughout the country. Due to education and
intervention, cocaine use has since declined. However, high rates of legal, psychiatric,
medical, and social problems related to cocaine use still exist, thus cocaine related
disorders remain an important public health issue.
Cocaine is an alkaloid derived from the shrub Erythroxylum coca, which is indigenous to South America, where the
leaves of the shrub are chewed by local inhabitants to obtain the stimulating effects (Fig. 20.9-1). The cocaine alkaloid was
first isolated in 1855 and first used as a local anesthetic in 1880. It is still used as a local anesthetic, especially for eye, nose,
and throat surgery, for which its vasoconstrictive and analgesic effects are helpful. In 1884, Sigmund Freud made a study
of cocaine’s general pharmacological effects and, for a period of time, according to his biographers, was addicted to the
drug. In the 1880s and 1890s, cocaine was widely touted as a cure for many ills and was listed in the 1899 Merck Manual. It
was the active ingredient in the beverage Coca-Cola until 1903. In 1914, however, once its addictive and adverse effects had
been recognized, cocaine was classified as a narcotic, along with morphine and heroin.
FIGURE 20.9-1
Cocaine is an alkaloid obtained from coca leaves.
Epidemiology
Cocaine Use.
In 2012, 1.5 million (0.6 percent) persons aged 12 years or older used
cocaine in the past month. Persons aged 18 to 25 (1.5 percent) had a higher rate of past
month cocaine use than persons aged 26 or older (0.5 percent) and youths aged 12 to 17
(0.9 percent). Males (0.8 percent) were twice as likely as females (0.4 percent) to have
used cocaine in the past year. Asians had the lowest rate of past year cocaine use (0.5
percent) compared with other racial or ethnic groups.
Cocaine Abuse and Dependence.
In 2012 more than 1.0 million (0.4 percent)
persons aged 12 or older met the criteria for abuse of, or dependence on, cocaine in the
past year. Persons aged 18 to 25 (0.9 percent) had the highest rate of past year cocaine
abuse or dependence, followed by persons aged 26 or older (0.4 percent) and youths
aged 12 to 17 (0.2 percent). Males (0.9 percent) were more than twice as likely as
females (0.4 percent) to have met the criteria for cocaine abuse or dependence. Blacks
(1.1 percent) and Hispanics (0.9 percent) had higher rates of cocaine abuse or
dependence than whites (0.5 percent), and the rate for Asians (0.1 percent) was lower
than that for blacks, Hispanics, whites, American Indians or Alaskan Natives (1.2
percent), and non-Hispanic persons who identified themselves with two or more races
(0.9 percent).
Crack Cocaine.
An estimated 1.1 million (0.4 percent) persons aged 12 or older
used crack cocaine in the past year, and 492,000 (0.2 percent) persons used crack
cocaine in the past month. Persons aged 18 to 25 (0.5 percent) had the highest rate of
past year crack use, followed by persons aged 26 or older (0.4 percent) and youths aged
12 to 17 (0.1 percent). Males (0.5 percent) were twice as likely as females (0.3 percent)
to have used crack cocaine in the past year. Asians had the lowest rate of past year
crack cocaine use (0.1 percent) compared with other racial or ethnic groups. Blacks (0.9
percent), whites (0.4 percent), Hispanics or Latinos (0.3 percent), and persons who
identified themselves with two or more non-Hispanic races (0.9 percent) had higher
rates of past year crack cocaine use than American Indians or Alaska Natives (0.2
percent) and Native Hawaiians or Other Pacific Islanders (0.1 percent).
Current cocaine use is on the decline, primarily because of increased awareness of
cocaine’s risks, as well as a comprehensive public campaign about cocaine and its
effects. The societal effects of the decrease in cocaine use, however, have been
somewhat offset by the frequent use over the past years of crack.
Comorbidity
As with other substance-related disorders, cocaine-related disorders are often
accompanied by additional psychiatric disorders. The development of mood disorders
and alcohol-related disorders usually follows the onset of cocaine-related disorders,
whereas anxiety disorders, antisocial personality disorder, and ADHD are thought to
precede the development of cocaine-related disorders. Most studies of comorbidity in
patients with cocaine-related disorders have shown that major depressive disorder,
bipolar II disorder, cyclothymic disorder, anxiety disorders, and antisocial personality
disorder are the most commonly associated psychiatric diagnoses. The percentages of
comorbidity in cocaine users are presented in Table 20.9-1.
Table 20.9-1
Additional Psychiatric Diagnoses among Cocaine Users Seeking Treatment
(New Haven Cocaine Diagnostic Study Results, Percentages)
Etiology
Genetic Factors.
The most convincing evidence to date of a genetic influence on
cocaine dependence comes from studies of twins. Monozygotic twins have higher
concordance rates for stimulant dependence (cocaine, amphetamines, and
amphetamine-like drugs) than dizygotic twins. The analyses indicate that genetic factors
and unique (unshared) environmental factors contribute about equally to the
development of stimulant dependence.
Sociocultural Factors.
Social, cultural, and economic factors are powerful
determinants of initial use, continuing use, and relapse. Excessive use is far more likely
in countries where cocaine is readily available. Different economic opportunities may
influence certain groups more than others to engage in selling illicit drugs, and selling is
more likely to be carried out in familiar communities than in communities where the
seller runs a high risk of arrest.
Learning and Conditioning.
Learning and conditioning are also considered
important in perpetuating cocaine use. Each inhalation or injection of cocaine yields a
“rush” and a euphoric experience that reinforces the antecedent drug-taking behavior. In
addition, the environmental cues associated with substance use become associated with
the euphoric state so that long after a period of cessation, such cues (e.g., white powder
and paraphernalia) can elicit memories of the euphoric state and reawaken craving for
cocaine.
In cocaine abusers (but not in normal controls), cocaine-related stimuli activate brain
regions subserving episodic and working memory and produce electroencephalography
(EEG) arousal (desynchronization). Increased metabolic activity in the limbic-related
regions, such as the amygdala, parahippocampal gyrus, and dorsolateral prefrontal
cortex, reportedly correlates with reports of craving for cocaine, but the degree of EEG
arousal does not.
Pharmacological Factors.
As a result of actions in the central nervous system
(CNS), cocaine can produce a sense of alertness, euphoria, and well-being. Users may
experience decreased hunger and less need for sleep. Performance impaired by fatigue is
usually improved. Some users believe that cocaine enhances sexual performance.
Neuropharmacology
Cocaine’s primary pharmacodynamic action related to its behavioral effects is competitive blockade of dopamine reuptake
by the dopamine transporter. This blockade increases the concentration of dopamine in the synaptic cleft and results in
increased activation of both dopamine type 1 (D1) and type 2 (D2) receptors. The effects of cocaine on the activity
mediated by D3, D4, and D5 receptors are not yet well understood, but at least one preclinical study has implicated the D3
receptor. Although the behavioral effects are attributed primarily to the blockade of dopamine reuptake, cocaine also
blocks the reuptake of norepinephrine and serotonin. The behavioral effects related to these activities are receiving
increased attention in the scientific literature. The effects of cocaine on cerebral blood flow and cerebral glucose use have
also been studied. Results in most studies generally showed that cocaine is associated with decreased cerebral blood flow
and possibly with the development of patchy areas of decreased glucose use.
The behavioral effects of cocaine are felt almost immediately and last for a relatively brief time (30 to 60 minutes); thus
users require repeated doses of the drug to maintain the feelings of intoxication. Despite the short-lived behavioral effects,
metabolites of cocaine can be present in the blood and urine for up to 10 days.
Cocaine has powerful addictive qualities. Because of its potency as a positive reinforcer of behavior, psychological
dependence on cocaine can develop after a single use. With repeated administration, both tolerance and sensitivity to
various effects of cocaine can arise, although the development of tolerance or sensitivity is apparently caused by many
factors and is not easily predicted. Physiological dependence on cocaine does occur, although cocaine withdrawal is mild
compared with withdrawal from opiates and opioids.
Researchers recently reported that positron emission tomography (PET) scans of the brains of patients being treated for
cocaine addiction show high activation in the mesolimbic dopamine system when addicts profoundly crave a drug.
Researchers exposed patients to cues that had previously caused them to crave cocaine, and patients described feelings of
intense cravings for the drug while PET scans showed activation in areas from the amygdala and the anterior cingulate to
the tip of both temporal lobes. Some researchers claim that the mesolimbic dopamine system is also active in patients
with nicotine addiction, and the same system has been linked to cravings for heroin, morphine, amphetamines, marijuana,
and alcohol.
The D2 receptors in the mesolimbic dopamine system have been held responsible for the heightened activity during
periods of craving. PET scans of patients recovering from cocaine addiction are reported to show a drop in neuronal
activity consistent with a lessened ability to receive dopamine, and the reduction in this ability, although it decreases over
time, is apparent as long as a year and a half after withdrawal. The pattern of reduced brain activity reflects the course of
the craving; between the third and fourth weeks of withdrawal, the activity is at its lowest level, and the risk of patient
relapse is highest. After about 1 year, the brains of former addicts are almost back to normal, although whether the
dopamine cells ever return to a completely normal state is debatable.
Methods of Use
Because drug dealers often dilute cocaine powder with sugar or procaine, street cocaine
varies greatly in purity. Cocaine is sometimes cut with amphetamine. The most common
method of using cocaine is inhaling the finely chopped powder into the nose, a practice
referred to as “snorting” or “tooting.” Other methods of ingesting cocaine are
subcutaneous or intravenous injection and smoking (freebasing). Freebasing involves
mixing street cocaine with chemically extracted pure cocaine alkaloid (the freebase) to
get an increased effect. Smoking is also the method used to ingest crack cocaine.
Inhaling is the least dangerous method of cocaine use; intravenous injection and
smoking are the most dangerous. The most direct methods of ingestion are often
associated with cerebrovascular diseases, cardiac abnormalities, and death. Although
cocaine can be taken orally, it is rarely ingested via this, the least effective, route.
Crack.
Crack, a freebase form of cocaine, is extremely potent. It is sold in small,
ready-to-smoke amounts, often called “rocks.” Crack cocaine is highly addictive; even
one or two experiences with the drug can cause intense craving for more. Users have
been known to resort to extremes of behavior to obtain the money to buy more crack.
Reports from urban emergency rooms have also associated extremes of violence with
crack abuse.
DIAGNOSIS AND CLINICAL FEATURES
Stimulant Use Disorder
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)
diagnostic criteria for stimulant use disorder are similar to the criteria used for other
substance use disorders (see page 621).
Amphetamine dependence can result in a rapid downward spiral of a person’s
abilities to cope with work- and family-related obligations and stresses. A person who
abuses amphetamines requires increasingly high doses of amphetamine to obtain the
usual high, and physical signs of amphetamine abuse (e.g., decreased weight and
paranoid ideas) almost always develop with continued abuse.
Mr. H, a 35-year-old married man, was admitted to a psychiatric hospital because
he felt persecuted by gang members who were out to kill him. He could not explain
why they wished to kill him, but he heard voices from people whom he suspected to be
mob drug dealers and they were discussing that they should kill him. He used
methamphetamine for several years, so he had dealt with drug dealers before. He
began using at age 27 at the persuasion of a friend to try it. After an injection of 20
mg, he felt good and powerful and his sleepiness and fatigue disappeared. After a few
tries Mr. H found that he could not stop using it. He constantly thought about how he
would obtain the drug and started increasing the dosage he used. During times that he
could not get methamphetamine, he felt lethargic and sleepy and became irritable and
dysphoric. Mr. H’s wife learned of his drug use and attempted to persuade him to stop
using it. He lost his job 2 months prior to his admission because he was repeatedly
abusive to work colleagues because he felt that they were trying to harm him. With no
income, Mr. H had to cut down his use of methamphetamine to only occasional usage.
He finally decided to quit when his wife threatened to divorce him. Once he stopped
using, he felt very tired, seemed gloomy, and often sat in his favorite chair and did
nothing. After a few weeks, Mr. H told his wife that he did not wish to leave the house
because he had heard dealers on the street talking about him. He wanted all doors and
windows locked, and he refused to eat in fear that the food may be poisoned.
On examination, Mr. H seemed withdrawn, only giving short answers to questions.
He was in clear consciousness and fully oriented and showed no marked impairment
of cognitive functions. Physical and neurological testing showed no abnormalities
except needle scars on his arms from methamphetamine injections. An EEG was
normal.
Clinically and practically, cocaine use disorder can be suspected in patients who
evidence unexplained changes in personality. Common changes associated with cocaine
use are irritability, impaired ability to concentrate, compulsive behavior, severe
insomnia, and weight loss. Colleagues at work and family members may notice a
person’s general and increasing inability to perform the expected tasks associated with
work and family life. The patient may show new evidence of increased debt or inability
to pay bills on time because of the large sums used to buy cocaine. Cocaine abusers
often excuse themselves from work or social situations every 30 to 60 minutes to find a
secluded place to inhale more cocaine. Because of the vasoconstricting effects of
cocaine, users almost always develop nasal congestion, which they may attempt to selfmedicate with decongestant sprays.
Mr. D, a 45-year-old married man, was referred by his therapist to a private
outpatient substance abuse treatment program for evaluation and treatment of a
possible cocaine problem. According to the therapist, Mr. D’s wife expressed concern
for a possible substance abuse problem on several occasions. A few days prior, Mr. D
admitted to the therapist and his wife that he “occasionally” used cocaine for the past
year. His wife insisted that he obtain treatment for his drug problem or else she would
file for divorce. Mr. D reluctantly conceded to treatment, but insisted that his cocaine
use was not a problem and that he felt capable of stopping without entering a
treatment program.
During the initial evaluation interview, Mr. D reported that he currently used
cocaine, intranasally, 3 to 5 days a week, and that this pattern has been continuing
for a year and a half. On average, he consumes a total of 1 to 2 grams of cocaine
weekly. He mostly uses cocaine at work, in his office or in the bathroom. He usually
started thinking about cocaine during his drive to work in the morning and once at
work was unable avoid thinking about the cocaine in his desk drawer. Despites his
attempts at distraction and postponing use, he usually takes his first line of cocaine
within an hour of arriving at work. On some days he will take another two to three
lines over the course of the day, but, on days where he is frustrated and stressed, he
may take a line or two every hour from morning until late afternoon. He rarely uses
cocaine at home and never uses in front of his wife or his three daughters. He
occasionally takes a line or two during a weekday evening or weekends at home
when everyone else is out of the house. He denies current use of alcohol or any other
illicit drug. He denies any history of alcohol or drug abuse and any history of
emotional or marital problems.
Stimulant Intoxication
The diagnostic criteria for stimulant intoxication emphasize behavioral and physical
signs and symptoms of stimulant use (Table 20.9-2). Persons use stimulants for their
characteristic effects of elation, euphoria, heightened self-esteem, and perceived
improvement on mental and physical tasks. With high doses, symptoms of intoxication
include agitation, irritability, impaired judgment, impulsive and potentially dangerous
sexual behavior, aggression, a generalized increase in psychomotor activity, and
potentially, symptoms of mania. The major associated physical symptoms are
tachycardia, hypertension, and mydriasis.
Table 20.9-2
Signs and Symptoms of Stimulant Intoxication
Mrs. T, a 45-year-old married business woman, was admitted to psychiatric service
after a 3-month period in which she became increasing mistrustful of others and
suspicious of business associates. She took statements from others out of context,
twisting their words, and making inappropriately hostile and accusatory comments.
On one occasion, Mrs. T physically attacked a coworker in a bar accusing her of
having an affair with her husband and plotting with other coworkers to kill her.
One year previously, Mrs. T was prescribed methylphenidate for narcolepsy due to
daily irresistible sleep attacks and episodes of sudden loss of muscle tone when she
became emotionally excited. After taking the medication, Mrs. T became
asymptomatic and was able to work effectively and have an active social life with
family and friends.
In the 5 months before admission, Mrs. T had been using increasingly large doses of
methylphenidate to maintain alertness late at night because of an increased amount
of work that could not be handled during the day. She reported that during this time
she often could feel her heart race and that she had trouble sitting still.
Mr. P, an 18-year-old man, was brought to a hospital emergency room via
ambulance in the middle of the night. He was accompanied by a friend who decided
to call an ambulance because he felt Mr. P was going to die. Mr. P was agitated and
argumentative, his breathing was irregular and rapid, his pulse was rapid, and his
pupils were dilated. His friend eventually admitted that they used a lot of cocaine that
evening.
When his mother arrived at the hospital, Mr. P’s condition had somewhat improved,
although his loud singing created a commotion in the emergency room. His mother
states Mr. P has some disciplinary problems; he is disobedient, resentful, and violently
argumentative. He had been arrested on a few occasions for shoplifting and for
driving while intoxicated. His mother suspected that Mr. P was using drugs due to his
behavior and because she heard him talk to his friends about drugs, however, she has
no direct proof of his use.
Within 24 hours, Mr. P was well and willing to talk. He boastfully stated that he
had been using alcohol and various drugs regularly since he was 13. It started with
just alcohol and marijuana, but once he entered high school and became acquainted
with older youths, he experimented with other drugs such as speed and cocaine. By the
time he was 16, he was using combinations of alcohol, speed, marijuana, and cocaine.
He settled on just cocaine after a year of mixing drugs.
Mr. P frequently skipped school and when he attended school he was usually
intoxicated. To support his habit, he acquired money in various schemes, such as
borrowing money from friends that he had no intention of paying back or stealing car
radios or stealing from his mother.
Despite his blatant admission of drug use, Mr. P denies having a problem. When
asked about his ability to control his drug use, he defensively replies “Of course I can.
No problem. I just don’t see any damn reason to stop.”
Stimulant Withdrawal
After stimulant intoxication, a “crash” occurs with symptoms of anxiety, tremulousness,
dysphoric mood, lethargy, fatigue, nightmares (accompanied by rebound rapid eye
movement [REM] sleep), headache, profuse sweating, muscle cramps, stomach cramps,
and insatiable hunger. The withdrawal symptoms generally peak in 2 to 4 days and are
resolved in 1 week. The most serious withdrawal symptom is depression, which can be
particularly severe after the sustained use of high doses of stimulants and which can be
associated with suicidal ideation or behavior. A person in the state of withdrawal can
experience powerful and intense cravings for cocaine, especially because taking cocaine
can eliminate the unpleasant withdrawal symptoms. Persons experiencing cocaine
withdrawal often attempt to self-medicate with alcohol, sedatives, hypnotics, or
antianxiety agents such as diazepam (Valium).
Stimulant Intoxication Delirium
Delirium associated with stimulant use generally results from high doses of a stimulant
or from sustained use, and so sleep deprivation affects the clinical presentation. The
combination of stimulants with other substances and the use of stimulants by a person
with preexisting brain damage can also cause development of delirium. It is not
uncommon for university students who are using amphetamines to cram for
examinations to exhibit this type of delirium.
Stimulant-Induced Psychotic Disorder
The hallmark of stimulant-induced psychotic disorder is the presence of paranoid
delusions and hallucinations, which occurs in up to 50 percent of stimulant users.
Auditory hallucinations are also common, but visual and tactile hallucinations are less
common than paranoid delusions. The sensation of bugs crawling beneath the skin
(formication) has been reported to be associated with cocaine use. The presence of these
symptoms depends on the dose, duration of use, and the user’s sensitivity to the
substance. Cocaine-induced psychotic disorders are most common with intravenous use
and crack users, and the psychotic symptoms are more common in men than in women.
The treatment of choice for amphetamine-induced psychotic disorder is the short-term
use of an antipsychotic medication such as haloperidol (Haldol).
Mr. H is a 20-year-old college student who was functioning well until the weeks of
his finals, when he began taking large amounts of cocaine because he felt he was
unprepared for his tests. He began having delusional beliefs that he was being
followed by the police and a detective at the request of his parents in order to spy on
him. He also believed that his roommate would give reports to the detective about his
study habits and social life. He was brought to the emergency room after he
threatened to harm his roommate if he continued to report on him.
During evaluation, Mr. P reported sleeplessness and auditory hallucinations that
told him that his roommate was conspiring against him. He was very agitated and
paced continuously. After admission to the hospital, Mr. P was given antipsychotics
and sleeping medications and recovered in 3 days.
Stimulant-Induced Mood Disorder
The DSM-5 allows for the diagnoses of stimulant-induced bipolar disorder and stimulantinduced depressive disorder, either of which can begin during either intoxication or
withdrawal. In general, intoxication is associated with manic or mixed mood features,
whereas withdrawal is associated with depressive mood features.
Stimulant-Induced Anxiety Disorder
The DSM-5 allows for the diagnosis of stimulant-induced anxiety disorder. The onset of
stimulant-induced anxiety disorder can also occur during intoxication or withdrawal.
Stimulants can induce symptoms similar to those seen in panic disorder, and phobic
disorders, in particular.
Stimulant-Induced Obsessive-Compulsive Disorder
The DSM-5 allows for the diagnosis of stimulant-induced obsessive-compulsive disorder.
The onset can occur during intoxication or withdrawal. After high doses of stimulants,
some individuals develop time-limited stereotyped behaviors or rituals (i.e., picking at
clothing, and arranging and rearranging items purposelessly) that share some features
with the type of compulsions seen in obsessive-compulsive disorder.
Stimulant-Induced Sexual Dysfunction
The DSM-5 allows for the diagnosis of stimulant-induced sexual dysfunction.
Amphetamines may be prescribed as an antidote to the sexual side effects of
serotonergic agents such as fluoxetine (Prozac), but stimulants are often misused by
persons to enhance sexual experiences. High doses and long-term use are associated
with erectile disorder and other sexual dysfunctions.
Stimulant-Induced Sleep Disorder
Stimulant-induced sleep disorder can begin during either intoxication or withdrawal,
and sleep dysfunction can vary depending on the onset. Stimulant intoxication can
produce insomnia and sleep deprivation, whereas persons undergoing stimulant
withdrawal can experience hypersomnolence and nightmares.
ADVERSE EFFECTS
Amphetamines
Physical.
Amphetamine abuse can produce adverse effects, the most serious of
which include cerebrovascular, cardiac, and gastrointestinal effects. Among the specific
life-threatening conditions are myocardial infarction, severe hypertension,
cerebrovascular disease, and ischemic colitis. A continuum of neurological symptoms,
from twitching to tetany to seizures to coma and death, is associated with increasingly
high amphetamine doses. Intravenous use of amphetamines can transmit human
immunodeficiency virus (HIV) and hepatitis and further the development of lung
abscesses, endocarditis, and necrotizing angiitis. Several studies have shown that
abusers of amphetamines knew little—or did not care—about safe-sex practices and the
use of condoms. The non–life-threatening adverse effects of amphetamine abuse include
flushing, pallor, cyanosis, fever, headache, tachycardia, palpitations, nausea, vomiting,
bruxism (teeth grinding), shortness of breath, tremor, and ataxia. Pregnant women who
use amphetamines often have babies with low birthweight, small head circumference,
early gestational age, and growth retardation.
Psychological.
The adverse psychological effects associated with amphetamine use
include restlessness, dysphoria, insomnia, irritability, hostility, and confusion.
Amphetamine use can also induce symptoms of anxiety disorders, such as generalized
anxiety disorder and panic disorder, as well as ideas of reference, paranoid delusions,
and hallucinations.
Cocaine
A common adverse effect associated with cocaine use is nasal congestion; serious
inflammation, swelling, bleeding, and ulceration of the nasal mucosa can also occur.
Long-term use of cocaine can also lead to perforation of the nasal septa. Freebasing and
smoking crack can damage the bronchial passages and the lungs. The intravenous use of
cocaine can result in infection, embolisms, and the transmission of human
immunodeficiency virus (HIV). Minor neurological complications with cocaine use
include the development of acute dystonia, tics, and migraine-like headaches. The major
complications of cocaine use, however, are cerebrovascular, epileptic, and cardiac.
About two thirds of these acute toxic effects occur within 1 hour of intoxication, about
one fifth occur in 1 to 3 hours, and the remainder occurs up to several days later.
Cerebrovascular Effects.
The most common cerebrovascular diseases associated
with cocaine use are nonhemorrhagic cerebral infarctions. When hemorrhagic
infarctions do occur, they can include subarachnoid, intraparenchymal, and
intraventricular hemorrhages. Transient ischemic attacks have also been associated with
cocaine use. Although these vascular disorders usually affect the brain, spinal cord
hemorrhages have also been reported. The obvious pathophysiological mechanism for
these vascular disorders is vasoconstriction, but other pathophysiological mechanisms
have also been proposed.
Seizures.
Seizures have been reported to account for 3 to 8 percent of cocainerelated emergency room visits. Cocaine is the substance of abuse most commonly
associated with seizures; the second most common substance is amphetamine. Cocaineinduced seizures are usually single events, although multiple seizures and status
epilepticus are also possible. A rare and easily misdiagnosed complication of cocaine use
is partial complex status epilepticus, which should be considered as a diagnosis in a
patient who seems to have cocaine-induced psychotic disorder with an unusually
fluctuating course. The risk of having cocaine-induced seizures is highest in patients with
a history of epilepsy who use high doses of cocaine as well as crack.
Cardiac Effects.
Myocardial infarctions and arrhythmias are perhaps the most
common cocaine-induced cardiac abnormalities. Cardiomyopathies can develop with
long-term use of cocaine, and cardioembolic cerebral infarctions can be a further
complication of cocaine-induced myocardial dysfunction.
Death.
High doses of cocaine are associated with seizures, respiratory depression,
cerebrovascular diseases, and myocardial infarctions—all of which can lead to death in
persons who use cocaine. Users may experience warning signs of syncope or chest pain
but may ignore these signs because of the irrepressible desire to take more cocaine.
Deaths have also been reported with the ingestion of “speedballs,” which are
combinations of opioids and cocaine.
Other Agents
Substituted Amphetamines.
MDMA (3,4-methylene-dioxymethamphetamine) is
one of a series of substituted amphetamines that also includes MDEA, MDA (3,4methylene-dioxyamphetamine), DOB (2,5-dimethoxy-4-bromoamphetamine), PMA
(paramethoxyamphetamine), and others. These drugs produce subjective effects
resembling those of amphetamine and LSD (lysergic acid diethylamide), and in that
sense, MDMA and similar analogues may represent a distinct category of drugs.
A methamphetamine derivative that came into use in the 1980s, MDMA was not technically subject to legal regulation at
the time. Although it has been labeled a “designer drug” in the belief that it was deliberately synthesized to evade legal
regulation, it was actually synthesized and patented in 1914. Several psychiatrists used it as an adjunct to psychotherapy
and concluded that it had value. At one time, it was advertised as legal and was used in psychotherapy for its subjective
effects. It was never approved by the FDA, however. Its use raised questions of both safety and legality, because the related
amphetamine derivatives MDA, DOB, and PMA had caused a number of overdose deaths, and MDA was known to cause
extensive destruction of serotonergic nerve terminals in the CNS. Using emergency scheduling authority, the Drug
Enforcement Agency made MDMA a Schedule I drug under the CSA, along with LSD, heroin, and marijuana. Despite its
illegal status, MDMA continues to be manufactured, distributed, and used in the United States, Europe, and Australia. Its
use is common in Australia and Great Britain at extended dances (“raves”) popular with adolescents and young adults.
MECHANISMS OF ACTION. The unusual properties of the drugs may be a consequence of the
different actions of the optical isomers: the R(–) isomers produce LSD-like effects and the
amphetamine-like properties are linked to S(+) isomers. The LSD-like actions, in turn,
may be linked to the capacity to release serotonin. The various derivatives may exhibit
significant differences in subjective effects and toxicity. Animals in laboratory
experiments will self-administer the drugs, suggesting prominent amphetamine-like
effects.
SUBJECTIVE EFFECTS. After taking usual doses (100 to 150 mg), MDMA users experience
elevated mood and, according to various reports, increased self-confidence and sensory
sensitivity; peaceful feelings coupled with insight, empathy, and closeness to persons;
and decreased appetite. Difficulty concentrating and an increased capacity to focus have
both been reported. Dysphoric reactions, psychotomimetic effects, and psychosis have
also been reported. Higher doses seem more likely to produce psychotomimetic effects.
Sympathomimetic effects of tachycardia, palpitation, increased blood pressure,
sweating, and bruxism are common. The subjective effects are reported to be prominent
for about 4 to 8 hours, but they may not last as long or may last longer, depending on
the dose and route of administration. The drug is usually taken orally but is also snorted
and injected. Both tachyphylaxis and some tolerance are reported by users.
TOXICITY. Although it is not as toxic as MDA, various somatic toxicities have been
attributed to MDMA use as well as fatal overdoses. It does not appear to be neurotoxic
when injected into the brains of animals, but it is metabolized to MDA in both animals
and humans. In animals, MDMA produces selective, long-lasting damage to serotonergic
nerve terminals. It is not certain if the levels of the MDA metabolite reached in humans
after the usual doses of MDMA suffice to produce lasting damage. Users of MDMA show
differences in neuroendocrine responses to serotonergic probes, and studies of former
MDMA users show global and regional decreases in serotonin transporter binding, as
measured by PET (Fig. 20.9-2).
FIGURE 20.9-2
Positron emission tomography (PET) images obtained 75 to 95 minutes postinjection of
[11C]McN5652 and [11C]DASB in a representative control subject and a representative
3,4-methylenedioxymethamphetamine (MDMA) subject, demonstrating the reductions in
serotonin transporter (SERT) binding in the MDMA subject with both radioligands. PET
images are normalized to a common maximum. (Reprinted from McCann UD, Szabo Z,
Seckin E, Rosenblatt P, Mathews WB. Quantitative PET studies of serotonin transporter
MDMA
users
and
controls
using
[11C]McN5652
and
[11C]DASB.
Neuropsychopharmacology. 2005;30[9]:1741, with permission.)
Currently, no established clinical uses exist for MDMA, although before its regulation, there were several reports of its
beneficial effects as an adjunct to psychotherapy.
Khat.
The fresh leaves of Catha edulis, a bush native to East Africa, have been used
as a stimulant in the Middle East, Africa, and the Arabian Peninsula for at least 1,000
years. Khat is still widely used in Ethiopia, Kenya, Somalia, and Yemen. The
amphetamine-like effects of khat have long been recognized, and although efforts to
isolate the active ingredient were first undertaken in the 19th century, only since the
1970s has cathinone (S[–] α-aminopropiophenone or S[–]2-amino-1-phenyl-1propanone) been identified as the substance responsible. Cathinone is a precursor
moiety that is normally enzymatically converted in the plant to the less-active entities
norephedrine and cathine (norpseudoephedrine), which explains why only the fresh
leaves of the plant are valued for their stimulant effects. Cathinone has most of the CNS
and peripheral actions of amphetamine and appears to have the same mechanism of
action. In humans, it elevates mood, decreases hunger, and alleviates fatigue. At high
doses, it can induce an amphetamine-like psychosis in humans. Because it is typically
absorbed buccally after chewing the leaf and because the alkaloid is metabolized
relatively rapidly, high toxic blood levels are rarely reached. Concern about khat use is
linked to its dependence-producing properties rather than to its acute toxicity. It is
estimated that five million doses are consumed each day, despite prohibition of its use in
a number of African and Arab countries.
In the 1990s, several clandestine laboratories began synthesizing methcathinone, a
drug with actions similar to those of cathinone. Known by a number of street names
(e.g., bath salts, “CAT,” “goob,” and “crank”), its popularity is primarily owing to its
ease of synthesis from ephedrine or pseudoephedrine, which were readily available until
placed under special controls. Methcathinone has been moved to Schedule I of the CSA.
The patterns of use, adverse effects, and complications closely resemble those reported
for amphetamine.
“Club Drugs”.
The use of a certain group of substances popularly called club drugs
is often associated with dance clubs, bars, and all-night dance parties (raves). The group
includes LSD, γ-hydroxybutyrate (GHB), ketamine, methamphetamine, MDMA (ecstasy),
and Rohypnol or “roofies” (flunitrazepam). These substances are not all in the same
drug class, and they do not produce the same physical or subjective effects. GHB,
ketamine, and Rohypnol have been called date rape drugs because they produce
disorienting and sedating effects, and often users cannot recall what occurred during all
or part of an episode under the influence of the drug. Hence, it is alleged that these
drugs might be surreptitiously placed in a beverage, or a person might be convinced to
take the drug and then not recall clearly what occurred after ingestion.
Emergency department mentions of GHB, ketamine, and Rohypnol are relatively few.
Of the club drugs, methamphetamine is the substance that accounts for the largest share
of treatment admissions.
TREATMENT AND REHABILITATION
Amphetamines
The treatment of amphetamine-related (or amphetamine-like) disorders shares with
cocaine-related disorders the difficulty of helping patients remain abstinent from the
drug, which is powerfully reinforcing and induces craving. An inpatient setting and the
use of multiple therapeutic methods (individual, family, and group psychotherapy) are
usually necessary to achieve lasting abstinence. The treatment of specific amphetamineinduced disorders (e.g., amphetamine-induced psychotic disorder and amphetamineinduced anxiety disorder) with specific drugs (e.g., antipsychotic and anxiolytics) may
be necessary on a short-term basis. Antipsychotics may be prescribed for the first few
days. In the absence of psychosis, diazepam (Valium) is useful to treat patients’
agitation and hyperactivity.
Physicians should establish a therapeutic alliance with patients to deal with the
underlying depression, personality disorder, or both. Because many patients are heavily
dependent on the drug, however, psychotherapy may be especially difficult.
Comorbid conditions, such as depression, may respond to antidepressant medication.
Bupropion (Wellbutrin) may be of use after patients have withdrawn from
amphetamine. It has the effect of producing feelings of well-being as these patients cope
with the dysphoria that may accompany abstinence.
Cocaine
Detoxification.
The cocaine withdrawal syndrome is distinct from that of opioids,
alcohol, or sedative-hypnotic agents, because no physiological disturbances necessitate
inpatient or residential drug withdrawal. Thus, it is generally possible to engage in a
therapeutic trial of outpatient withdrawal before deciding whether a more intensive or
controlled setting is required for patients unable to stop without help in limiting their
access to cocaine. Patients withdrawing from cocaine typically experience fatigue,
dysphoria, disturbed sleep, and some craving; some may experience depression. No
pharmacological agents reliably reduce the intensity of withdrawal, but recovery over a
week or two is generally uneventful. It may take longer, however, for sleep, mood, and
cognitive function to recover fully.
Most cocaine users do not come to treatment voluntarily. Their experience with the
substance is too positive, and the negative effects are perceived as too minimal, to
warrant seeking treatment. Those who do not seek treatment often have polysubstancerelated disorder, fewer negative consequences associated with cocaine use, fewer workor family-related obligations, and increased contact with the legal system and with
illegal activities.
The major hurdle to overcome in the treatment of cocaine-related disorders is the
user’s intense craving for the drug. Although animal studies have shown that cocaine is a
powerful inducer of self-administration, these studies have also shown that animals limit
their use of cocaine when negative reinforcers are experimentally linked to the cocaine
intake. In humans, negative reinforcers may take the form of work and family-related
problems brought on by cocaine use. Therefore, clinicians must take a broad treatment
approach and include social, psychological, and perhaps biological strategies in the
treatment program.
Attaining abstinence from cocaine in patients may require complete or partial
hospitalization to remove them from the usual social settings in which they had obtained
or used cocaine. Frequent, unscheduled urine testing is almost always necessary to
monitor patients’ continued abstinence, especially in the first weeks and months of
treatment. Relapse prevention therapy (RPT) relies on cognitive and behavioral
techniques in addition to hospitalization and outpatient therapy to achieve the goal of
abstinence.
Psychosocial Therapies.
Psychological intervention usually involves individual,
group, and family modalities. In individual therapy, therapists should focus on the
dynamics leading to cocaine use, the perceived positive effects of the cocaine, and other
ways to achieve these effects. Group therapy and support groups, such as Narcotics
Anonymous, often focus on discussions with other persons who use cocaine and on
sharing experiences and effective coping methods. Family therapy is often an essential
component of the treatment strategy. Common issues discussed in family therapy are
the ways the patient’s past behavior has harmed the family and the responses of family
members to these behaviors. Therapy should also focus, however, on the future and on
changes in the family’s activities that may help the patient stay off the drug and direct
energies in different directions. This approach can be used on an outpatient basis.
NETWORK THERAPY. Network therapy was developed as a specialized type of combined
individual and group therapy to ensure greater success in the office-based treatment of
addicted patients. Network therapy uses both psychodynamic and cognitive-behavioral
approaches to individual therapy while engaging the patient in a group support
network. The group, composed of the patient’s family and peers, is used as a therapeutic
network joining the patient and therapist at intervals in therapy sessions. The approach
promotes group cohesiveness as a vehicle for engaging patients in this treatment. This
network is managed by the therapist to provide cohesiveness and support and to
promote compliance with treatment. Although network therapy has not received
systematic controlled evaluation, it is frequently applied in the psychiatric practice
because it is one of the few manualized approaches that has been designed for use by
individual practitioners in an office setting.
Pharmacological Adjuncts.
Presently, no pharmacological treatments produce
decreases in cocaine use comparable to the decreases in opioid use seen when heroin
users are treated with methadone, levomethadyl acetate (ORLAAM) (commonly called La-acetylmethadol [LAAM]), or buprenorphine (Buprenex). A variety of pharmacological
agents, most of which are approved for other uses, have been, and are being, tested
clinically for the treatment of cocaine dependence and relapse.
Cocaine users presumed to have preexisting ADHD or mood disorders have been
treated with methylphenidate (Ritalin) and lithium (Eskalith), respectively. Those drugs
are of little or no benefit in patients without the disorders, and clinicians should adhere
strictly to maximal diagnostic criteria before using either of them in the treatment of
cocaine dependence. In patients with ADHD, slow-release forms of methylphenidate
may be less likely to trigger cocaine craving, but the impact of such pharmacotherapy
on cocaine use remains to be demonstrated.
Many pharmacological agents have been explored on the premise that chronic cocaine use alters the function of multiple
neurotransmitter systems, especially the dopaminergic and serotonergic transmitters regulating hedonic tone, and that
cocaine induces a state of relative dopaminergic deficiency. Although the evidence for such alterations in dopaminergic
function has been growing, it has been difficult to demonstrate that agents theoretically capable of modifying dopamine
function can alter the course of treatment.
Tricyclic antidepressant drugs yielded some positive results when used early in treatment with minimally drugdependent patients; however, they are of little or no use inducing abstinence in moderate or severe cases.
Also tried but not confirmed effective in controlled studies are other antidepressants, such as bupropion, monoamine
oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), antipsychotics, lithium, several different
calcium channel inhibitors, and anticonvulsants. One study found that 300 mg a day of phenytoin (Dilantin) reduced
cocaine use; this study requires further replication.
Several agents are being developed that have not been tried in human studies. These include agents that would
selectively block or stimulate dopamine receptor subtypes (e.g., selective D1 agonists) and drugs that can selectively block
the access of cocaine to the dopamine transporters but still permit the transporters to remove cocaine from the synapse.
Another approach is aimed at preventing cocaine from reaching the brain by using antibodies to bind cocaine in the
bloodstream (a so-called “cocaine vaccine”). Such cocaine-binding antibodies do reduce the reinforcing effects of cocaine
in animal models. Also under study are catalytic antibodies that accelerate the hydrolysis of cocaine, and
butyrylcholinesterase (pseudocholinesterase), which appears to hydrolyze cocaine selectively and is normally present in
the body.
Vigabatrin is a drug that has been used as a treatment for refractory pediatric epilepsy, which appears to function by
significantly elevating brain γ-aminobutyric acid (GABA) levels. In animals, vigabatrin was also noted to attenuate cocaine,
nicotine, heroin, alcohol, and methamphetamine-induced increases in extracellular nucleus accumbens dopamine as well
as drug-seeking behaviors associated with these biochemical changes. Preliminary clinical studies suggest efficacy for the
treatment of cocaine and methamphetamine dependence. Large scale clinical trials for this indication are needed, however.
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10 - 20.10 Tobacco Related Disorders
20.10 Tobacco-Related Disorders
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20.10 Tobacco-Related Disorders
Tobacco use disorder is among the most prevalent, deadly, and costly of substance
dependencies. It is also one of the most ignored, particularly by psychiatrists, because
despite recent research that shows commonalities between tobacco dependence and
other substance use disorders, tobacco dependence differs from other substance
dependencies in unique ways. Tobacco does not cause behavioral problems; therefore,
few tobacco-dependent persons seek or are referred for psychiatric treatment. Tobacco
is a legal drug and most persons who stop tobacco use have done so without treatment.
Thus a common, but erroneous, view is that, unlike alcohol and other illicit drugs, most
smokers do not need treatment.
Several recent events may reverse the reluctance of psychiatrists to play a role in
treating tobacco dependence: (1) the growing recognition that most psychiatric patients
smoke and many die from tobacco dependence; (2) remaining smokers will be more and
more likely to have psychiatric problems, which suggests that many need more intensive
treatments; and (3) the development of multiple pharmacological agents to aid smokers
in quitting.
EPIDEMIOLOGY
The 2004 Monitoring the Future Survey concluded that, despite the demonstrated health
risk associated with cigarette smoking, young Americans continue to smoke. However,
30-day smoking rates among high school students declined from peaks reached in 1996
for eighth-graders (21.0 percent) and tenth-graders (30.4 percent) and in 1997 for
seniors (36.5 percent). In 2011, 30-day rates reached the lowest levels ever reported by
Monitoring the Future surveys for eighth-graders (6.1 percent), tenth-graders (11.8
percent), and twelfth-graders (18.7 percent), with tenth-graders showing the most
significant decline. Of high school seniors, 19 percent reported smoking during the
month preceding their responses to the survey.
The decrease in smoking rates among young Americans corresponds to several years
in which increased proportions of teens said they believe a “great” health risk is
associated with cigarette smoking and expressed disapproval of smoking one or more
packs of cigarettes a day. Students’ personal disapproval of smoking had risen for some
years. In 2011, 88 percent of eighth-graders, 85.8 percent of tenth-graders, and 83
percent of twelfth-graders stated that they “disapprove” or “strongly disapprove” of
people smoking one or more packs of cigarettes per day. In addition, eighth-graders and
tenth-graders reported significant increases in the perceived harmfulness of smoking one
or more packs of cigarettes per day.
The World Health Organization (WHO) estimates that there are 1 billion smokers
worldwide, and they smoke 6 trillion cigarettes a year. The WHO also estimates that
tobacco kills more than 3 million persons each year. Although the number of persons in
the United States who smoke is decreasing, the number of persons smoking in
developing countries is increasing. The rate of quitting smoking has been highest among
well-educated white men and lowest among women, blacks, teenagers, and those with
low levels of education.
Tobacco is smoked most commonly in cigarettes, and then, in descending order,
cigars, snuff, chewing tobacco, and in pipes. About 3 percent of all persons in the
United States currently use snuff or chewing tobacco, and about 6 percent of young
adults ages 18 to 25 use those forms of tobacco.
Currently, about 19.3 percent of Americans smoke. The mean age of onset of smoking
is 16 years, and few persons start smoking after 20. Dependence features appear to
develop quickly. Classroom and other programs to prevent initiation are only mildly
effective, but increased taxation does decrease initiation.
More than 75 percent of smokers have tried to quit, and about 40 percent try to quit
each year. On a given attempt, only 30 percent remain abstinent for even 2 days, and
only 5 to 10 percent stop permanently. Most smokers make 5 to 10 attempts, however,
so eventually 50 percent of “ever smokers” quit. In the past, 90 percent of successful
attempts to quit involved no treatment. With the advent of over-the-counter (OTC) and
non-nicotine medications in 1998, about one third of all attempts involved the use of
medication.
In terms of the diagnosis of tobacco use disorder per se, about 20 percent of the
population develops tobacco dependence at some point, making it one of the most
prevalent psychiatric disorders. Approximately 85 percent of current daily smokers are
tobacco dependent. Tobacco withdrawal occurs in about 50 percent of smokers who try
to quit.
According to the Centers of Disease Control and Prevention (CDC), regional
differences exist in smoking throughout the United States. The 13 states with the highest
prevalence of current smoking are Kentucky, West Virginia, Oklahoma, Mississippi,
Indiana, Missouri, Alabama, Louisiana, Nevada, Tennessee, Alaska, North Carolina, and
Ohio. Those states with lowest prevalence are Utah, California, Washington,
Massachusetts, Rhode Island, District of Columbia, Hawaii, Maryland, Connecticut, New
Hampshire, New Jersey, and Arizona. Utah had the lowest prevalence for men (10.6
percent) and for women (7.9 percent).
Education
Level of education attainment correlated with tobacco use. Of adults who had not
completed high school, 37 percent smoked cigarettes, whereas only 17 percent of college
graduates smoked.
Psychiatric Patients
Psychiatrists must be particularly concerned and knowledgeable about tobacco
dependence because of the high proportion of psychiatric patients who smoke.
Approximately 50 percent of all psychiatric outpatients, 70 percent of outpatients with
bipolar I disorder, almost 90 percent of outpatients with schizophrenia, and 70 percent
of patients with substance use disorder smoke. Moreover, data indicate that patients
with depressive disorders or anxiety disorders are less successful in their attempts to quit
smoking than other persons; thus, a holistic health approach for these patients probably
includes helping them address their smoking habits in addition to the primary mental
disorder. The high percentage of patients with schizophrenia who smoke has been
attributed to tobacco’s ability to reduce their extraordinary sensitivity to outside sensory
stimuli and to increase their concentration. In that sense, such patients are selfmonitoring to relieve distress.
Death
Death is the primary adverse effect of cigarette smoking. Tobacco use is associated with
approximately 400,000 premature deaths each year in the United States—25 percent of
all deaths. The causes of death include chronic bronchitis and emphysema (51,000
deaths), bronchogenic cancer (106,000 deaths), 35 percent of fatal myocardial
infarctions (115,000 deaths), cerebrovascular disease, cardiovascular disease, and
almost all cases of chronic obstructive pulmonary disease and lung cancer. The
increased use of chewing tobacco and snuff (smokeless tobacco) has been associated
with the development of oropharyngeal cancer, and the resurgence of cigar smoking is
likely to lead to an increase in the occurrence of this type of cancer.
Researchers have found that 30 percent of cancer deaths in the United States are
caused by tobacco smoke, the single most lethal carcinogen in the United States.
Smoking (mainly cigarette smoking) causes cancer of the lung, upper respiratory tract,
esophagus, bladder, and pancreas and probably of the stomach, liver, and kidney.
Smokers are eight times more likely than nonsmokers to develop lung cancer, and lung
cancer has surpassed breast cancer as the leading cause of cancer-related deaths in
women. Even secondhand smoke (discussed below) causes a few thousand cancer deaths
each year in the United States, about the same number as are caused by radon exposure.
Despite these staggering statistics, smokers can dramatically lower their chances of
developing smoke-related cancers simply by quitting.
NEUROPHARMACOLOGY
The psychoactive component of tobacco is nicotine, which affects the central nervous
system (CNS) by acting as an agonist at the nicotinic subtype of acetylcholine receptors.
About 25 percent of the nicotine inhaled during smoking reaches the bloodstream,
through which nicotine reaches the brain within 15 seconds. The half-life of nicotine is
about 2 hours. Nicotine is believed to produce its positive reinforcing and addictive
properties by activating the dopaminergic pathway projecting from the ventral
tegmental area to the cerebral cortex and the limbic system. In addition to activating
this dopamine reward system, nicotine causes an increase in the concentrations of
circulating norepinephrine and epinephrine and an increase in the release of
vasopressin, β-endorphin, adrenocorticotropic hormone (ACTH), and cortisol. These
hormones are thought to contribute to the basic stimulatory effects of nicotine on the
CNS.
DIAGNOSIS
Tobacco Use Disorder
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorder (DSM-5)
includes a diagnosis for tobacco use disorder characterized by craving, persistent and
recurrent use, tolerance, and withdrawal if tobacco is stopped. Dependence on tobacco
develops quickly, probably because nicotine activates the ventral tegmental area
dopaminergic system, the same system affected by cocaine and amphetamine. The
development of dependence is enhanced by strong social factors that encourage
smoking in some settings and by the powerful effects of tobacco company advertising.
Persons are likely to smoke if their parents or siblings smoke and serve as role models.
Several recent studies have also suggested a genetic diathesis toward tobacco
dependence. Most persons who smoke want to quit and have tried many times to quit
but have been unsuccessful.
Tobacco Withdrawal
The DSM-5 does not have a diagnostic category for tobacco intoxication, but it does
have a diagnostic category for nicotine withdrawal. Withdrawal symptoms can develop
within 2 hours of smoking the last cigarette; they generally peak in the first 24 to 48
hours and can last for weeks or months. The common symptoms include an intense
craving for tobacco, tension, irritability, difficulty concentrating, drowsiness and
paradoxical trouble sleeping, decreased heart rate and blood pressure, increased
appetite and weight gain, decreased motor performance, and increased muscle tension.
A mild syndrome of tobacco withdrawal can appear when a smoker switches from
regular to low-nicotine cigarettes.
CLINICAL FEATURES
Behaviorally, the stimulatory effects of nicotine produce improved attention, learning,
reaction time, and problem-solving ability. Tobacco users also report that cigarette
smoking lifts their mood, decreases tension, and lessens depressive feelings. Results of
studies of the effects of nicotine on cerebral blood flow (CBF) suggest that short-term
nicotine exposure increases CBF without changing cerebral oxygen metabolism, but
long-term nicotine exposure decreases CBF. In contrast to its stimulatory CNS effects,
nicotine acts as a skeletal muscle relaxant.
Adverse Effects
Nicotine is a highly toxic alkaloid. Doses of 60 mg in an adult are fatal secondary to
respiratory paralysis; doses of 0.5 mg are delivered by smoking an average cigarette. In
low doses the signs and symptoms of nicotine toxicity include nausea, vomiting,
salivation, pallor (caused by peripheral vasoconstriction), weakness, abdominal pain
(caused by increased peristalsis), diarrhea, dizziness, headache, increased blood
pressure, tachycardia, tremor, and cold sweats. Toxicity is also associated with an
inability to concentrate, confusion, and sensory disturbances. Nicotine is further
associated with a decrease in the user’s amount of rapid eye movement (REM) sleep.
Tobacco use during pregnancy has been associated with an increased incidence of low
birth weight babies and an increased incidence of newborns with persistent pulmonary
hypertension.
Health Benefits of Smoking Cessation
Smoking cessation has major and immediate health benefits for persons of all ages and
provides benefits for persons with and without smoking-related diseases. Former
smokers live longer than those who continue to smoke. Smoking cessation decreases the
risk for lung cancer and other cancers, myocardial infarction, cerebrovascular diseases,
and chronic lung diseases. Women who stop smoking before pregnancy or during the
first 3 to 4 months of pregnancy reduce their risk for having low birth weight infants to
that of women who never smoked. The health benefits of smoking cessation
substantially exceed any risks from the average 5-pound (2.3 kg) weight gain or any
adverse psychological effects after quitting.
TREATMENT
Strategies to prevent tobacco use in children and adolescents are listed in Table 20.10-1.
For those who already smoke, psychiatrists should advise them to quit smoking. For
patients who are ready to stop smoking, it is best to set a “quit date.” Most clinicians
and smokers prefer abrupt cessation, but because no good data indicate that abrupt
cessation is better than gradual cessation, patient preference for gradual cessation
should be respected. Brief advice should focus on the need for medication or group
therapy, weight gain concerns, high-risk situations, making cigarettes unavailable, and
so forth. Because relapse is often rapid, the first follow-up phone call or visit should be 2
to 3 days after the quit date. These strategies have been shown to double self-initiated
quit rates (Table 20.10-2).
Table 20.10-1
Primary Care Interventions to Prevent Tobacco Use in Children and
Adolescents
Table 20.10-2
Typical Quit Rates of Common Therapies
Ms. H was a 45-year-old patient with schizophrenia who smoked 35 cigarettes per
day. She began her cigarette use at approximately 20 years of age during the
prodromal stages of her first psychotic break. During the first 20 years of treatment,
no psychiatrist or physician advised her to stop smoking.
When the patient was 43 years of age, her primary physician recommended
smoking cessation. Ms. H attempted to stop on her own but lasted only 48 hours,
partly because her housemates and friends smoked. During a routine medication
check, her psychiatrist recommended that she stop smoking, and Ms. H described her
prior attempts. The psychiatrist and Ms. H discussed ways to avoid smokers and had
the patient announce her intent to quit and request that her friends try not to smoke
around her and to offer encouragement for her attempt to quit. The psychiatrist also
noted that Ms. H became irritable, slightly depressed, and restless, and that she had
insomnia during prior cessation attempts, and thus recommended medications. Ms. H
chose to use a nicotine patch plus nicotine gum as needed.
The psychiatrist had Ms. H call 2 days after her attempt to quit smoking. At this
point, Ms. H stated that the patch and gum were helping. One week later, the patient
returned after having relapsed back to smoking. The psychiatrist praised Ms. H for
not smoking for 4 days. He suggested that Ms. H contact him again if she wished to
try to stop again. Seven months later, during another medication check, the
psychiatrist again asked Ms. H to consider cessation, but she was reluctant.
Two months later, Ms. H called and said she wished to try again. This time, the
psychiatrist and Ms. H listed several activities that she could do to avoid being around
friends who smoked, phoned Ms. H’s boyfriend to ask him to assist her in stopping,
asked the nurses on the inpatient ward to call Ms. H to encourage her, plus enrolled
Ms. H in a support group for the next 4 weeks. This time the psychiatrist prescribed
the non-nicotine medication varenicline (Chantix). Ms. H was followed with 15minute visits for each of the first 3 weeks. She had two “slips” but did not go back to
smoking and remained an ex-smoker. (Adapted from John R. Hughes, M.D.)
Psychosocial Therapies
Behavior therapy is the most widely accepted and well-proved psychological therapy for
smoking. Skills training and relapse prevention identify high-risk situations and plan
and practice behavioral or cognitive coping skills for those situations in which smoking
occurs. Stimulus control involves eliminating cues for smoking in the environment.
Aversive therapy has smokers smoke repeatedly and rapidly to the point of nausea,
which associates smoking with unpleasant, rather than pleasant, sensations. Aversive
therapy appears to be effective but requires a good therapeutic alliance and patient
compliance.
Hypnosis.
Some patients benefit from a series of hypnotic sessions. Suggestions
about the benefits of not smoking are offered and assimilated into the patient’s
cognitive framework as a result. Posthypnotic suggestions that cause cigarettes to taste
bad or to produce nausea when smoked are also used.
Psychopharmacological Therapies
Nicotine Replacement Therapies.
All nicotine replacement therapies double
cessation rates, presumably because they reduce nicotine withdrawal. These therapies
can also be used to reduce withdrawal in patients on smoke-free wards. Replacement
therapies use a short period of maintenance of 6 to 12 weeks, often followed by a
gradual reduction period of another 6 to 12 weeks.
Nicotine polacrilex gum (Nicorette) is an OTC product that releases nicotine via
chewing and buccal absorption. A 2 mg variety for those who smoke fewer than 25
cigarettes a day and a 4 mg variety for those who smoke more than 25 cigarettes a day
are available. Smokers are to use one to two pieces of gum per hour up to a maximum
of 24 pieces per day after abrupt cessation. Venous blood concentrations from the gum
are one third to one half the between-cigarette levels. Acidic beverages (coffee, tea,
soda, and juice) should not be used before, during, or after gum use because they
decrease absorption. Compliance with the gum has often been a problem. Adverse
effects are minor and include bad taste and sore jaws. About 20 percent of those who
quit use the gum for long periods, but 2 percent use gum for longer than a year; longterm use does not appear to be harmful. The major advantage of nicotine gum is its
ability to provide relief in high-risk situations.
Nicotine lozenges (Commit) deliver nicotine and are also available in 2 mg and 4 mg
forms; they are useful especially for patients who smoke a cigarette immediately on
awakening. Generally, 9 to 20 lozenges a day are used during the first 6 weeks, with
decrease in dosage thereafter. Lozenges offer the highest level of nicotine of all nicotine
replacement products. Users must suck the lozenge until dissolved and not swallow it.
Side effects include insomnia, nausea, heartburn, headache, and hiccups.
Nicotine patches, also sold OTC, are available in a 16-hour, no-taper preparation
(Nicotrol) and a 24- or 16-hour tapering preparation (Nicoderm CQ). Patches are
administered each morning and produce blood concentrations about half those of
smoking. Compliance is high, and the only major adverse effects are rashes and, with
24-hour wear, insomnia. Using gum and patches in high-risk situations increases quit
rates by another 5 to 10 percent. No studies have been done to determine the relative
efficacies of 24- or 16-hour patches or of taper and no-taper patches. After 6 to 12
weeks, the patch is discontinued because it is not for long-term use.
Nicotine nasal spray (Nicotrol), available only by prescription, produces nicotine
concentrations in the blood that are more similar to those from smoking a cigarette, and
it appears to be especially helpful for heavily dependent smokers. The spray, however,
causes rhinitis, watering eyes, and coughing in more than 70 percent of patients.
Although initial data suggested abuse liability, further trials have not found this.
The nicotine inhaler, a prescription product, was designed to deliver nicotine to the
lungs, but the nicotine is actually absorbed in the upper throat. It delivers 4 mg per
cartridge and resultant nicotine levels are low. The major asset of the inhaler is that it
provides a behavioral substitute for smoking. The inhaler doubles quit rates. These
devices require frequent puffing—about 20 minutes to extract 4 mg of nicotine—and
have minor adverse effects.
Non-nicotine Medications.
Non-nicotine therapy may help smokers who object
philosophically to the notion of replacement therapy and smokers who fail replacement
therapy. Bupropion (Zyban) (marketed as Wellbutrin for depression) is an
antidepressant medication that has both dopaminergic and adrenergic actions.
Bupropion is started at 150 mg per day for 3 days and increased to 150 mg twice a day
for 6 to 12 weeks. Daily dosages of 300 mg double quit rates in smokers with and
without a history of depression. In one study, combined bupropion and nicotine patch
had higher quit rates than either alone. Adverse effects include insomnia and nausea,
but these are rarely significant. Seizures have not occurred in smoking trials. Of interest,
nortriptyline (Pamelor) appears to be effective for smoking cessation and is
recommended as a second-line drug.
Clonidine (Catapres) decreases sympathetic activity from the locus ceruleus and, thus,
is thought to abate withdrawal symptoms. Whether given as a patch or orally, 0.2 to 0.4
mg a day of clonidine appears to double quit rates; however, the scientific database for
the efficacy of clonidine is neither as extensive nor as reliable as that for nicotine
replacement; also, clonidine can cause drowsiness and hypotension. Some patients
benefit from benzodiazepine therapy (10 to 30 mg per day) for the first 2 to 3 weeks of
abstinence.
A nicotine vaccine that produces nicotine-specific antibodies in the brain is under
investigation at the National Institute on Drug Abuse (NIDA).
Combined Psychosocial and Pharmacological Therapy
Several studies have shown that combining nicotine replacement and behavior therapy
increases quit rates over either therapy alone.
Smoke-Free Environment
Secondhand smoke can contribute to lung cancer death and coronary heart disease in
adult nonsmokers. Each year, an estimated 3,000 lung cancer deaths and 62,000 deaths
from coronary artery disease in adult nonsmokers are attributed to secondhand smoke.
Among children, secondhand smoke is implicated in sudden infant death syndrome, low
birth weight, chronic middle ear infections, and respiratory illnesses (e.g., asthma,
bronchitis, and pneumonia). Two national health objectives for 2010 are to reduce
cigarette smoking among adults to 12 percent and the proportion of nonsmokers
exposed to environment tobacco smoke to 45 percent.
Involuntary exposure to secondhand smoke remains a common public health hazard
that is preventable by appropriate regulatory policies. Bans on smoking in public places
reduce exposure to secondhand smoke and the number of cigarettes smoked by smokers.
Support is nearly universal for bans in schools and day-care centers and strong support
for bans in indoor work areas and restaurants. Clean indoor air policies are one way to
change social norms about smoking and reduce tobacco consumption. Bans on outdoor
smoking in areas, such as public parks, are increasing and in 2006 one municipality in
California banned smoking entirely within city limits except in one’s own home or car
and windows had to remain closed. Currently over 600 municipalities have smoke-free
park laws, including New York City, which banned smoking in all its public parks,
including famed Central Park, in 2011.
REFERENCES
Arehart-Treichel J. Smoking high on list of suicide-risk factors. Psychiatr News. 2011;46:16.
Benowitz NL. Neurobiology of nicotine addiction: Implications for smoking cessation treatment. Am J Med. 2008;121:S3.
Blazer DG, Wu LT. Patterns of tobacco use and tobacco-related psychiatric morbidity and substance use among middle-aged
and older adults in the United States. Aging Men Health. 2012;16:296.
Dome P, Lazary J, Kalapos MP, Rihmer Z. Smoking, nicotine and neuropsychiatric disorders. Neurosci Biobehav Rev.
2010;34:295.
Fiore M, Jean C, Baker T, Bailey W, Benowitz N: Treating Tobacco Use and Dependence: Clinical Practice Guideline.
Washington, DC: US Public Health Service; 2008.
Hatsukami DK, Benowitz NL, Donny E, Henningfield J, Zeller M. Nicotine reduction: Strategic research plan. Nicotine Tob
Res. 2013;15(6):1003–1013.
Hughes J. Nicotine-related disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of
Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:1353.
Husten CG, Deyton LR. Understanding the Tobacco Control Act: Efforts by the US Food and Drug Administration to make
tobacco-related morbidity and mortality part of the USA’s past, not its future. Lancet. 2013;381(9877):1570–1580.
Lakhan SE, Kirchgessner A. Anti-inflammatory effects of nicotine in obesity and ulcerative colitis. J Translation Med.
2011;9:129.
Margerison-Zilko C, Cubbin C. Socioeconomic disparities in tobacco-related health outcomes across racial/ethnic groups in
the United States: National Health Interview Survey 2010. Nicotine Tob Res. 2013;15(6):1161–1165.
Mushtaq N, Beebe LA, Vesely SK, Neas BR. A multiple motive/multi-dimensional approach to measure smokeless tobacco
dependence. Addictive Behaviors, 2014; 39(3): 622–629.
Roman J. Nicotine-induced fibronectin expression might represent a common mechanism by which tobacco promotes
lung cancer progression and obstructive airway disease. Proc Am Thorac Soc. 2012;9:85.
Warbrick T, Mobascher A, Brinkmeyer J, Musso F, Stoecker T, Shah NJ, Vossel S, Winterer G. Direction and magnitude of

11 - 20.11 Anabolic Androgenic Steroid Abuse
20.11 Anabolic-Androgenic Steroid Abuse
nicotine effects on the fMRI BOLD response are related to nicotine effects on behavioral performance.
Psychopharmacology. 2011;215:333.
Weinberger AH, Desai RA, McKee SA. Nicotine withdrawal in U.S. smokers with current mood, anxiety, alcohol use, and
substance use disorders. Drug Alcohol Depend. 2010;108:7.
Weinberger AH, Sofuoglu M. The impact of cigarette smoking on stimulant addiction. Am J Drug Abuse. 2009;35:12.
20.11 Anabolic-Androgenic Steroid Abuse
The anabolic-androgenic steroids (AAS) are a family of hormones that includes
testosterone, the natural male hormone, which together with numerous synthetic
analogs of testosterone have been developed over the last 70 years (Table 20.11-1).
These drugs exhibit various degrees of anabolic (muscle building) and androgenic
(masculinizing) effects; none of these drugs display purely anabolic effects in the
absence of androgenic effects. It is important not to confuse the anabolic-androgenic
steroids (AAS) (testosterone-like hormones) with corticosteroids (cortisol-like hormones
such as hydrocortisone and prednisone). Corticosteroids are hormones secreted by the
adrenal gland, rather than by the testes. Corticosteroids have no muscle-building
properties and, hence, little abuse potential; they are widely prescribed to treat
numerous inflammatory conditions such as poison ivy or asthma. AAS, by contrast, have
only limited legitimate medical applications, such as in the treatment of hypogonadal
men, the wasting syndrome associated with human immunodeficiency virus (HIV)
infection, and a few specific diseases such as hereditary angioedema and Fanconi’s
anemia. AAS, however, are widely used illicitly, especially by boys and young men
seeking to gain increased muscle mass and strength, either for athletic purposes or
simply to improve personal appearance.
Table 20.11-1
Examples of Commonly Used Anabolic Steroids
AAS does not have its own diagnostic category in the fifth edition of the American Psychiatric Association’s Diagnostic
and Statistical Manual of Mental Disorders (DSM-5); rather it is coded as one of the other or unknown substance related
disorders.
EPIDEMIOLOGY
Use of AAS is widespread among men in the United States, but are much less frequently
used by women. Approximately 890,000 American men and approximately 190,000
American women reported having used AAS at some time during their lives.
Approximately 286,000 men and 26,000 women are estimated to use steroids each year.
Among this number, nearly one third, or 98,000, were between 12 and 17 years of age.
Various studies of high school students in the United States have produced even higher
estimates of the prevalence of anabolic steroid use among adolescents. Across studies of
high school students, it is estimated that 3 to 12 percent of males and 0.5 to 2.0 percent
of females have used AAS during their lifetimes.
The current high rates of steroid use among younger individuals appear to represent
an important shift in the epidemiology of steroid use. In the 1970s, use of these drugs
was largely confined to competition bodybuilders, other elite weight-training athletes,
and elite athletes in other sports. Since then, however, it appears that an increasing
number of young men, and occasionally even young women, may be using these drugs
purely to enhance personal appearance rather than for any athletic purpose.
PHARMACOLOGY
All steroid drugs—including AAS, estrogens, and corticosteroids—are synthesized in vivo
from cholesterol and resemble cholesterol in their chemical structure. Testosterone has a
four-ring chemical structure containing 19 carbon atoms (Fig. 20.11-1).
FIGURE 20.11-1
Molecular structure of testosterone.
Normal testosterone plasma concentrations for men range from 300 to 1,000 ng/dL.
Generally, 200 mg of testosterone cypionate taken every 2 weeks restores physiological
testosterone concentrations in a hypogonadal male. A eugonadal male who initiates
physiological dosages of testosterone has no net gain in testosterone concentrations
because exogenously administered AAS shut down endogenous testosterone production
via feedback inhibition of the hypothalamic-pituitary-gonadal axis. Consequently, illicit
users take higher than therapeutic dosages to achieve supraphysiological effects. The
dose–response curve for anabolic effects may be logarithmic, which could explain why
illicit users generally take 10 to 100 times the therapeutic dosages. Doses in this range
are most easily achieved by taking combinations of oral and injected AAS, which illicit
AAS users often do. Transdermal testosterone, available by prescription for testosterone
replacement therapy, may also be used.
Therapeutic Indications
The AAS are indicated primarily for testosterone deficiency (male hypogonadism),
hereditary angioedema (a congenital skin disorder), and some uncommon forms of
anemia caused by bone marrow or renal failure. In women, AAS are given, although not
as first-choice agents, for metastatic breast cancer, osteoporosis, endometriosis, and
adjunctive treatment of menopausal symptoms. In men, they have been used
experimentally as a male contraceptive and for treating major depressive disorder and
sexual disorders in eugonadal men. Recently, they have been used to treat wasting
syndromes associated with acquired immunodeficiency syndrome (AIDS). Controlled
studies have also suggested that testosterone has antidepressant effects in some men
infected with HIV with major depressive disorder, and is also a supplementary
(augmentation) treatment in some depressed men with low endogenous testosterone
levels who are refractory to conventional antidepressants.
Adverse Reactions
The most common adverse medical effects of AAS involve the cardiovascular, hepatic,
reproductive, and dermatological systems.
The AAS produce an adverse cholesterol profile by increasing levels of low-density
lipoprotein cholesterol and decreasing levels of high-density lipoprotein cholesterol.
High-dose use of AAS can also activate hemostasis and increase blood pressure. Isolated
case reports of myocardial infarction, cardiomyopathy, left ventricular hypertrophy,
and stroke among users of AAS, including fatalities, have appeared,
Among the AAS-induced endocrine effects in men are testicular atrophy and sterility,
both usually reversible after discontinuing AAS, and gynecomastia, which may persist
until surgical removal. In women, shrinkage of breast tissue, irregular menses
(diminution or cessation), and masculinization (clitoral hypertrophy, hirsutism, and
deepened voice) can occur. Masculinizing effects in women may be irreversible.
Androgens taken during pregnancy could cause masculinization of a female fetus.
Dermatological effects include acne and male pattern baldness. Abuse of AAS by
children has led to concerns that AAS-induced premature closure of bony epiphyses could
cause shortened stature. Other uncommon adverse effects include edema of the
extremities caused by water retention, exacerbation of tic disorders, sleep apnea, and
polycythemia.
ETIOLOGY
The major reason for taking illicit AAS is to enhance either athletic performance or
physical appearance. Taking AAS is reinforced because they can produce the athletic
and physical effects that users desire, especially when combined with proper diet and
training. Further reinforcement derives from winning competitions and from social
admiration for physical appearance. AAS users also perceive that they can train more
intensively for longer durations with less fatigue and with decreased recovery times
between workouts.
The dramatic effects of AAS on muscle growth are illustrated in Figure 20.11-2, which
compares a “natural” bodybuilder who has never used these drugs with a bodybuilder of
identical height and body fat who has used AAS extensively.
FIGURE 20.11-2
Physical effects of anabolic steroid use. The photographs compare a “natural”
bodybuilder who has never used anabolic steroids (left) with a man who has used large
doses of anabolic steroids over several years (right). Both men are 67 inches tall and
have 7 percent body fat. The man on the left weighs 170 lbs and represents
approximately the maximum degree of muscularity obtainable without drugs. His fatfree mass index is 25.4 kg/m2 by the formula of Elana Kouri, et al. The man on the right
weighs 213 lbs and has a fat-free mass index of 31.7 kg/m2. Note the muscle
hypertrophy from steroid use is particularly marked in the upper body in the pectoralis,
deltoid, trapezius, and biceps muscles. Any man significantly more muscular than the
man on the left has almost certainly abused anabolic steroids. (Courtesy of H.G. Pope
M.D.)
Although the anabolic or muscle-building properties of AAS are clearly important to
those seeking to enhance athletic performance and physical appearance, psychoactive
effects may also be important in the persistent and dependent use of AAS. Anecdotally,
some AAS users report feelings of power, aggressiveness, and euphoria, which become
associated with, and can reinforce, AAS taking.
In general, males are more likely to take AAS than females, and athletes are more
likely to take AAS than nonathletes. Some male and female weight lifters may have
muscle dysmorphia, a form of body dysmorphic disorder in which the individual feels
that he or she is not sufficiently muscular and lean.
DIAGNOSIS AND CLINICAL FEATURES
Steroids may initially induce euphoria and hyperactivity. After relatively short periods,
however, their use can become associated with increased anger, arousal, irritability,
hostility, anxiety, somatization, and depression (especially during times when steroids
are not used). Several studies have demonstrated that 2 to 15 percent of anabolic steroid
abusers experience hypomanic or manic episodes, and a smaller percentage may have
clearly psychotic symptoms. Also disturbing is a correlation between steroid abuse and
violence (“roid rage” in the parlance of users). Steroid abusers with no record of
antisocial behavior or violence have committed murders and other violent crimes.
Steroids are addictive substances. When abusers stop taking steroids, they can become
depressed, anxious, and concerned about the physical state of their bodies. Some
similarities have been noted between athletes’ views of their muscles and the views of
patients with anorexia nervosa about their bodies; to an observer, both groups seem to
distort realistic assessment of the body.
Iatrogenic addiction is a consideration in view of the increasing number of geriatric
patients who are receiving testosterone from their physicians in an attempt to increase
libido and reverse some aspects of aging.
Mr. A is a 26-year-old single man. He is 69 inches tall and presently weighs 204
pounds, with a body fat of 11 percent. He reports that he began lifting weights at age
17, at which time he weighed 155 pounds. About 2 years after beginning his weight
lifting, he began taking AAS, which he obtained through a friend at his gymnasium.
His first “cycle” (course) of AAS, lasting for 9 weeks, involved methandienone
(Methanabol), 30 mg a day, orally, and testosterone cypionate, 600 mg a week,
intramuscularly. During these 9 weeks he gained 20 pounds of muscle mass. He was so
pleased with these results that he took five further cycles of AAS over the course of the
next 6 years. During his most ambitious cycle, approximately 1 year ago, he used
testosterone cypionate, 600 mg per week; nandrolone decanoate, 400 mg a week;
stanozolol (Winstrol), 12 mg a day; and oxandrolone (Anavar), 10 mg a day.
During each of the cycles Mr. A has noted euphoria, irritability, and grandiose
feelings. These symptoms were most prominent during his most recent cycle, when he
felt “invincible.” During this cycle he also noted a decreased need for sleep, racing
thoughts, and a tendency to spend excessive amounts of money. For example, he
impulsively purchased a $2,700 stereo system when he realistically could not afford to
spend more than $500. He also became uncharacteristically irritable with his
girlfriend, and on one occasion put his fist through the side window of her car during
an argument, an act inconsistent with his normally mild-mannered personality. After
this cycle of AAS ended, he became mildly depressed for about 2 months.
Mr. A has used a number of drugs to lose weight in preparation for bodybuilding
contests. These include ephedrine, amphetamine, triiodothyronine, and thyroxin.
Recently, he has also begun to use the opioid agonist–antagonist nalbuphine
intravenously (IV) to treat muscle aches from weight lifting. He also used oral opioids,
such as controlled-release oxycodone (OxyContin), at least once a week. He uses oral
opioids sometimes to treat muscle aches, but often simply to get high. He reports that
use of nalbuphine and other opioids is widespread among other AAS users of his
acquaintance.
Mr. A exhibits characteristic features of muscle dysmorphia. He checks his
appearance dozens of times a day in mirrors, or when he sees his reflection in a store
window or even in the back of a spoon. He becomes anxious if he misses even one day
of working out at the gym, and acknowledges that his preoccupation with weight
lifting has cost him both social and occupational opportunities. Although he has a 48inch chest and 19-inch biceps, he has frequently declined invitations to go to the beach
or a swimming pool for fear that he would look too small when seen in a bathing suit.
He is anxious because he has lost some weight since the end of his previous cycle of
AAS and is eager to resume another cycle of AAS in the near future. (Adapted from
Harrison G. Pope, Jr., M.D., and Kirk J. Brower, M.D.)
TREATMENT
Abstinence is the treatment goal of choice for patients manifesting AAS abuse or
dependence. To the extent that users of AAS abuse other addictive substances (including
alcohol), traditional treatment approaches for substance-related disorders may be used.
Nevertheless, AAS users may differ from other addicted patients in several ways that
have implications for treatment. First, the euphorigenic and reinforcing effects of AAS
may only become apparent after weeks or months of use in conjunction with intensive
exercising. When compared with immediately and passively reinforcing drugs, such as
cocaine, heroin, and alcohol, AAS use may entail more delayed gratification. Second,
AAS users may manifest greater commitment to culturally endorsed values of physical
fitness, success, victory, and goal directness than users of other illicit drugs. Finally, AAS
users are often preoccupied with their physical attributes and may rely excessively on
these attributes for self-esteem. Treatment therefore depends on a therapeutic alliance
that is based on a thorough and nonjudgmental understanding of the patient’s values
and motivations for using AAS.
AAS Withdrawal
Supportive therapy and monitoring are essential for treating AAS withdrawal because
suicidal depressions can occur. Hospitalization may be required when suicidal ideation is
severe. Patients should be educated about the possible course of withdrawal and
reassured that symptoms are time-limited and manageable. Antidepressant agents are
best reserved for patients whose depressive symptomatology persists for several weeks
after AAS discontinuation and who meet criteria for major depressive disorder. Selective
serotonin reuptake inhibitors (SSRIs) are the preferred agents because of their favorable
adverse effect profile and their effectiveness in the only reported case series of treated
AAS users with major depressive disorder. Physical withdrawal symptoms are not lifethreatening
and
do
not
ordinarily
require
pharmacotherapy.
Nonsteroidal
antiinflammatory drugs (NSAIDs) may be useful to treat musculoskeletal pain and
headaches.
ANABOLIC STEROID–INDUCED MOOD DISORDERS
Irritability, aggressiveness, hypomania, and frank mania associated with anabolic
steroid use probably represent one of the most important public health issues associated
with these drugs. Although athletes using these drugs have long recognized that
syndromes of anger and irritability could be associated with AAS use, these syndromes
were little recognized in the scientific literature until the late 1980s and 1990s. Since
then, a series of observational field studies of athletes has suggested that some AAS users
develop prominent hypomanic or even manic symptoms during AAS use.
A possible serious consequence of AAS-induced mood disorders may be violent or even
homicidal behavior. Several published reports have anecdotally described individuals
with no apparent history of psychiatric disorder, no criminal record, and no history of
violence, who committed violent crimes, including murder, while under the influence of
AAS. In a number of cases, AAS use has been cited in criminal trials as a possible
mitigating factor in the defense of such individuals. Although a causal link is difficult to
establish in these cases, evidence of AAS use has frequently been presented in forensic
settings as a possible mitigating factor in criminal behavior.
Depressive syndromes induced by AAS have occurred and suicide is a risk. A brief and
self-limited syndrome of depression occurs on AAS withdrawal, probably as a result of
the depression of the hypothalamic-pituitary-gonadal axis after exogenous AAS
administration.
ANABOLIC STEROID–INDUCED PSYCHOTIC DISORDER
Psychotic symptoms are rare in association with anabolic steroid use, but they have
been described in a few cases, primarily in individuals who were using the equivalent of
more than 1,000 mg of testosterone a week. Usually, these symptoms have consisted of
grandiose or paranoid delusions, generally occurring in the context of a manic episode,
although occasionally occurring in the absence of a frank manic syndrome. In most
cases reported, psychotic symptoms have disappeared promptly (within a few weeks)
after the discontinuation of the offending agent, although temporary treatment with
antipsychotic agents was sometimes required.
OTHER ANABOLIC STEROID–RELATED DISORDERS
Symptoms of anxiety disorders, such as panic disorder and social phobia can occur
during AAS use. AAS use may serve as a “gateway to the use of opioid agonist or
antagonists, such as nalbuphine, or to use of frank opioid agonists, such as heroin.” A
study of men admitted for substance dependence treatment in Massachusetts produced
similar findings.
DEHYDROEPIANDROSTERONE AND ANDROSTENEDIONE
Dehydroepiandrosterone (DHEA), a precursor hormone for both estrogens and
androgens, is available over the counter. Recent years have seen an interest in DHEA
for improving cognition, depression, sex drive, and general well-being in elderly adults.
Some reports suggest that DHEA in dosages of 50 to 100 mg per day increases the sense
of physical and social well-being in women aged 40 to 70 years. Reports also exist of
androgenic effects, including irreversible hirsutism, hair loss, voice deepening, and other
undesirable sequelae. In addition, DHEA has at least a theoretical potential of
enhancing tumor growth in persons with latent, hormone-sensitive malignancies, such
as prostate, cervical, and breast cancer. Despite its significant popularity, few controlled
data exist on the safety or efficacy of DHEA.
REFERENCES
Achar S, Rostamian A, Narayan SM. Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood
pressure, left ventricular dimensions, and rhythm. Am J Cardiol. 2010;106(6):893.
Baggish AL, Weiner RB, Kanayama G, Hudson JI, Picard MH, Hutter AM Jr., Pope HJ Jr.. Long-term anabolic-androgenic
steroid use is associated with left ventricular dysfunction. Circulation Heart Fail. 2010;3:472.
Basile JR, Binmadi NO, Zhou H, Yang Y-H, Paoli A, Proia P. Supraphysiological doses of performance enhancing anabolicandrogenic steroids exert direct toxic effects on neuron-like cells. Front Cell Neurosci. 2013;7:69.
Caraci F, Pistarà V, Corsaro A, Tomasello F, Giuffrida ML, Sortino MA, Nicoletti F, Copani A. Neurotoxic properties of the
anabolic androgenic steroids nandrolone and methandrostenolone in primary neuronal cultures. J Neurosci Res.
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segmental glomerulosclerosis after anabolic steroid abuse. J Am Soc Nephrol. 2010;21:163.
Kanayama G, Brower KJ, Wood RI, Hudson JI, Pope HG Jr.. Issues for DSM-V: Clarifying the diagnostic criteria for
anabolic–androgenic steroid dependence. Am J Psychiatry. 2009;166:642.
Kanayama G, Hudson JI, Pope HG. Demographic and psychiatric features of men with anabolic–androgenic steroid
dependence: a comparative study. Drug Alcohol Depend. 2009;102:130.
Kanayama G, Hudson JI, Pope HG Jr.. Illicit anabolic–androgenic steroid use. Horm Behav. 2010;58:111.
Kanayama G, Hudson JI, Pope HG Jr.. Long-term psychiatric and medical consequences of anabolic–androgenic steroid
abuse: a looming public health concern? Drug Alcohol Depend. 2008;98:1.
Kanayama G, Kean J, Hudson JI, Pope HG, Jr. Cognitive deficits in long-term anabolic-androgenic steroid users. Drug
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performance- and image-enhancing drugs. Drug Alcohol Rev. 2008;27:679.
Pope HG Jr, Brower KJ. Anabolic-androgenic steroid abuse. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s
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Pope HG Jr., Kanayama G, Hudson JI. Risk Factors for illicit anabolic-androgenic steroid use in male weightlifters: A crosssectional cohort study. Biol Psychiatry. 2012;71:254.

12 - 20.12 Other Substance Use and Addictive Disor
20.12 Other Substance Use and Addictive Disorders
Rodrigues R, Ramos S, Almeida N. Anabolic androgenic steroids in psychiatric practice. Eur Neuropsychopharmacol.
2012;22:S403.
Sagoe D, Molde H, Andreassen CS, Torsheim T, Pallesen S. The global epidemiology of anabolic-androgenic steroid use: A
meta-analysis and meta-regression analysis. Annals of Epidemiology. 2014;24(5):383–398.
Santamarina RD, Besocke AG, Romano LM, Ioli PL, Gonorazky SE. Ischemic stroke related to anabolic abuse. Clin
Neuropharmacol. 2008;31(2):80.
20.12 Other Substance Use and Addictive Disorders
This section considers a diverse set of drugs not covered in the previous sections that are
not easily categorized and grouped with other substances. The fifth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-5) includes a diagnostic
category for these substances called unknown or unspecified substance-related disorders.
Some of these are discussed in the following.
γ-HYDROXYBUTYRATE
γ-Hydroxybutyrate (GHB) is a naturally occurring neurotransmitter in the brain that is
related to sleep regulation. GHB increases dopamine levels in the brain. In general, GHB
is a central nervous system (CNS) depressant with effects through the endogenous opioid
system. It is used to induce anesthesia and long-term sedation, but its unpredictable
duration of action limits its use. GHB has been evaluated recently for the treatment of
alcohol and opioid withdrawal and narcolepsy.
Until 1990, GHB was sold in U.S. health food stores, and body builders used it as a
steroid alternative. Reports indicate, however, that GHB is abused for its intoxicating
effects and consciousness-altering properties. It is variously referred to as “GBH” and
“liquid ecstasy,” and it is sold illicitly in various forms (e.g., powder and liquid). Similar
chemicals, which the body converts to GBH, include γ-butyrolactone (GBL) and 1,4butanediol. Adverse effects include nausea, vomiting, respiratory problems, seizures,
coma, and death. In some reports, GHB abuse has been linked to a syndrome similar to
Wernicke-Korsakoff syndrome.
NITRITE INHALANTS
The nitrite inhalants include amyl, butyl, and isobutyl nitrites, all of which are called
“poppers” in popular jargon. The intoxication syndromes seen with nitrites can differ
markedly from the syndromes seen with the standard inhalant substances, such as
lighter fluid and airplane glue. Nitrite inhalants are used by persons seeking the
associated mild euphoria, altered sense of time, feeling of fullness in the head, and,
possibly, increased sexual feelings. The nitrite compounds are used by some gay men
and users of other drugs to heighten sexual stimulation during orgasm and, in some
cases, to relax the anal sphincter for penile penetration. Under such circumstances, a
person may use the substance for a few or a dozen times within several hours.
Adverse reactions include a toxic syndrome characterized by nausea, vomiting,
headache, hypotension, drowsiness, and irritation of the respiratory tract. Some
evidence indicates that nitrite inhalants can adversely affect immune function. Because
sildenafil (Viagra) and its congeners are lethal when combined with nitrite compounds,
persons at risk should be cautioned never to use the two together.
NITROUS OXIDE
Nitrous oxide, commonly known as “laughing gas,” is a widely available anesthetic
agent that is subject to abuse because of its ability to produce feelings of
lightheadedness and of floating, sometimes experienced as pleasurable or specifically as
sexual. With long-term abuse patterns, nitrous oxide use has been associated with
delirium and paranoia. Female dental assistants exposed to high levels of nitrous oxide
have reportedly experienced reduced fertility.
A 35-year-old male dentist with no history of other substance problems complained
of problems with nitrous oxide abuse for 10 years. This had begun as experimentation
with what he had considered a harmless substance. His rate of use increased over
several years, however, eventually becoming almost daily for months at a time. He
felt a craving before sessions of use. Then, using the gas while alone in his office, he
immediately felt numbness, a change in his temperature and heart rate, and
alleviation of depressed feelings. “Things would go through my mind. Time was
erased.” He sometimes fell asleep. Sessions might last a few minutes or up to 8 hours.
They ended when the craving and euphoria ended. He had often tried to stop or cut
down, sometimes consulting a professional about the problem.
OTHER SUBSTANCES
Nutmeg
Nutmeg can be ingested in a number of preparations. When nutmeg is taken in
sufficiently high doses, it can induce depersonalization, derealization, and a feeling of
heaviness in the limbs. In sufficiently high doses, morning glory seeds can produce a
syndrome resembling that seen with lysergic acid diethylamide (LSD), characterized by
altered sensory perceptions and mild visual hallucinations.
Catnip
Catnip can produce cannabis-like intoxication in low doses and LSD-like intoxication in
high doses.
Betel Nuts
Betel nuts, when chewed, can produce a mild euphoria and a feeling of floating in
space.
Kava
Kava, derived from a pepper plant native to the South Pacific, produces sedation and
incoordination and is associated with hepatitis, lung abnormalities, and weight loss.
Over-the-Counter Drugs
Some persons abuse over-the-counter and prescription medications, such as cortisol,
antiparkinsonian agents, and antihistamines.
Ephedra
Ephedra, a natural substance found in herbal tea, acts like epinephrine and, when
abused, produces cardiac arrhythmia and fatalities.
Chocolate
A controversial possible substance of abuse is chocolate derived from the cacao bean.
Anandamide, an ingredient in chocolate, stimulates the same receptors as marijuana.
Other compounds in chocolate include tryptophan, the precursor of serotonin, and
phenylalanine, an amphetamine-like substance, both of which improve mood. So-called
chocoholics may be self-medicating because of a depressive diathesis.
POLYSUBSTANCE-RELATED DISORDER
Substance users often abuse more than one substance. A diagnosis of polysubstance
dependence is appropriate if, for a period of at least 12 months, a person has repeatedly
used substances from at least three categories (not including nicotine and caffeine),
even if the diagnostic criteria for a substance-related disorder are not met for any single
substance, as long as, during this period, the criteria for substance dependence have
been met for the substances considered as a group.
TREATMENT AND REHABILITATION
Treatment approaches for the substances covered in this section vary according to
substances, patterns of abuse, availability of psychosocial support systems, and patients’
individual features. Two major treatment goals for substance abuse have been
determined: the first is abstinence from the substance; and the second is the physical,
psychiatric, and psychosocial well-being of the patient. Significant damage has often
been done to a patient’s support systems during prolonged periods of substance abuse.
For a patient to stop a pattern of substance abuse successfully, adequate psychosocial
supports must be in place to foster the difficult change in behavior.

13 - 20.13 Gambling Disorder
20.13 Gambling Disorder
In some rare cases, it may be necessary to initiate treatment on an inpatient unit.
Although an outpatient setting is more desirable than an inpatient setting, the
temptations available to an outpatient for repeated use may present too high a hurdle
for the initiation of treatment. Inpatient treatment is also indicated in the case of severe
medical or psychiatric symptoms, a history of failed outpatient treatments, a lack of
psychosocial supports, or a particularly severe or long-term history of substance abuse.
After an initial period of detoxification, patients need a sustained period of
rehabilitation. Throughout treatment, individual, family, and group therapies can be
effective. Education about substance abuse and support for patients’ efforts are essential
factors in treatment.
REFERENCES
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intracranial self-stimulation in rats. I. 2014;231(1):199–207.
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2009:1237.
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20.13 Gambling Disorder
Gambling disorder is characterized by persistent and recurrent maladaptive gambling
that causes economic problems and significant disturbances in personal, social, or
occupational functioning. Aspects of the maladaptive behavior include (1) a
preoccupation with gambling; (2) the need to gamble with increasing amounts of money
to achieve the desired excitement; (3) repeated unsuccessful efforts to control, cut back,
or stop gambling; (4) gambling as a way to escape from problems; (5) gambling to
recoup losses; (6) lying to conceal the extent of the involvement with gambling; (7) the
commission of illegal acts to finance gambling; (8) jeopardizing or losing personal and
vocational relationships because of gambling; and (9) a reliance on others for money to
pay off debts.
Previous editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) include pathological gambling
disorder in the impulse-control disorder category because of patient’s preoccupation or compulsion to gamble. However,
the criteria for the disorder are structured more like a substance-related or addiction disorder than an impulse-control
disorder, with the need to gamble with increased amounts of money to achieve desired excitement (tolerance) and feelings
of irritability and restlessness when attempting to reduce or stop gambling (withdrawal). Substance use is often a common
comorbidity with gambling. Thus, in the fifth edition of the DSM (DSM-5), gambling disorder is included in the section on
substance use and addictive disorders and is diagnosed as a non–substance-related disorder.
EPIDEMIOLOGY
Although comprehensive worldwide statistics have yet to be compiled, excellent local
studies all point to a 3 to 5 percent rate of problem gamblers in the general population
and an approximate 1 percent rate of individuals meeting the requirements for
gambling disorder. Problem gambling is more common in men and young adults than in
women and older adults; however, escalation has been noted in the poor, notably poor
minorities; adolescents; elderly retirees; and women. One of three pathological gamblers
is now female: it has been suggested that women are gambling more because of an
increased presence in the workplace that provides them with more cash. These groups
are still underserved with regard to research and treatment. The prevalence of gambling
disorder in individuals who have a substance use disorder is higher, with various surveys
showing rates of 10 to 18 percent of patients with substance abuse being pathological
gamblers.
As every type of gambling has become increasingly accessible over the last few
decades, the rate of normal and pathological gambling has risen spectacularly,
especially in locales with legalized gambling. The most popular types of gambling are
numbers/lotto (62.2 percent), slot machines or bingo (48.9 percent), gambling at a
casino (44.7 percent), and office sports pools (44.3 percent) (Table 20.13-1). The least
popular are betting on sports with a bookie or parlay card, internet gambling, and
speculating on high-risk investments.
Table 20.13-1
Lifetime Prevalence of Gambling Types
Family histories of pathological gamblers show an increased rate of substance abuse
(particularly alcoholism) and depressive disorders. A parent or influential relative of the
patient often has been a problem or pathological gambler. The family circle is likely to
be competitively and materialistically oriented, evincing intense admiration for money
and associated symbols of success. In this respect, compulsive gambling has been called
the dark side of the American dream.
COMORBIDITY
Significant comorbidity occurs between pathological gambling and mood disorders
(especially, major depression and bipolarity) and other substance use and addictive
disorders (notably, alcohol and stimulant abuse and caffeine and tobacco dependence).
Comorbidity
also
exists
with
attention-deficit/hyperactivity
disorder
(ADHD)
(particularly in childhood), various personality disorders (notably, narcissistic,
antisocial, and borderline personality disorders), and disruptive, impulse control, and
conduct disorders. Although many pathological gamblers have obsessive personality
traits, full-blown obsessive-compulsive disorder (OCD) is uncommon in this group.
ETIOLOGY
Psychosocial Factors
Several factors may predispose persons to develop the disorder: loss of a parent by
death, separation, divorce, or desertion before a child is 15 years of age; inappropriate
parental discipline (absence, inconsistency, or harshness); exposure to, and availability
of, gambling activities for adolescents; a family emphasis on material and financial
symbols; and a lack of family emphasis on saving, planning, and budgeting.
Psychoanalytic theory has focused on a number of core character difficulties. Sigmund
Freud suggested that compulsive gamblers have an unconscious desire to lose, and
gamble to relieve unconscious feelings of guilt. Another suggestion is that the gamblers
are narcissists, whose grandiose and omnipotent fantasies lead them to believe they can
control events and even predict their outcome. Learning theorists view uncontrolled
gambling as resulting from erroneous perceptions about control of impulses.
Biological Factors
Several studies have suggested that gamblers’ risk-taking behavior may have an
underlying neurobiological cause. These theories have centered on both serotonergic and
noradrenergic receptor systems. Male pathological gamblers may have subnormal 3methoxy-4-hydroxyphenyl glycol (MHPG) concentrations in plasma, increased MHPG
concentrations in the cerebrospinal fluid (CSF), and increased urinary output of
norepinephrine. Evidence also implicates serotonergic regulatory dysfunction in the
pathological gambler. Chronic gamblers have low platelet monoamine oxidase (MAO)
activity, a marker of serotonin activity, also linked to difficulties with inhibition. Further
studies are needed to confirm these findings.
DIAGNOSIS AND CLINICAL FEATURES
In addition to the features already described, pathological gamblers often appear
overconfident, somewhat abrasive, energetic, and free spending. They often show
obvious signs of personal stress, anxiety, and depression. They commonly have the
attitude that money is both the cause of, and the solution to all their problems. As their
gambling increases, they are usually forced to lie to obtain money and to continue
gambling while hiding the extent of their gambling. They make no serious attempt to
budget or save money. When their borrowing resources are strained, they are likely to
engage in antisocial behavior to obtain money for gambling. Their criminal behavior is
typically nonviolent, such as forgery, embezzlement, or fraud, and they consciously
intend to return or repay the money. Complications include alienation from family
members and acquaintances, the loss of life accomplishments, suicide attempts, and
association with fringe and illegal groups. Arrest for nonviolent crimes may lead to
imprisonment.
Gerry was a 35-year-old former auto dealership owner. Two of his uncles were
compulsive gamblers, and his paternal grandfather was hospitalized with major
depressive illness. He played poker and had been a racecourse habitué since the age
of 15 years. He had dropped out of college after a few months and become a car sales
representative. Soon he was promoted to showroom manager and then went out on
his own. By age 32 years, he was a multimillionaire owner of a dealership chain,
happily married with two children.
Gerry continued to gamble frequently. He was a successful weekend sports bettor,
as well as a consistent winner at weekly gin rummy and poker games and occasional
jaunts to Las Vegas and Atlantic City.
In the context of his wife giving birth to a stillborn child, Gerry started going to
casinos more often, gradually increasing the size of bets at blackjack and craps. His
sport wagers also escalated. His games at home gradually became boring—“there was
zilch action.” He began frequenting an illegal local poker parlor that featured highstake action.
Over several years, Gerry slipped into a typical gambling spiral. He accumulated
several million dollars in debts and lied to family and colleagues about his
whereabouts. He raided business and personal accounts, including his children’s
college funds, maxed out credit cards, and borrowed from loan sharks at exorbitant
rates. He grew profoundly depressed and seriously thought of killing himself in a car
crash so that his insurance would “take care of my family after I am gone.”
Gerry’s dire situation was unmasked when his Porsche was repossessed one Sunday
morning. Initially his wife threatened to divorce him. However, a wealthy relative
intervened and bailed him out. He swore never to gamble again, entered Gamblers
Anonymous, and within 2 months resumed his frantic chasing.
Over the next decade, Gerry underwent four more episodes of recovery and relapse.
His wife divorced him, he lost his dealerships, and he had to declare bankruptcy.
Gerry finally enrolled in a pilot dual-diagnostic recovery program, where he was
diagnosed with atypical bipolar disorder. His treatment included Gamblers
Anonymous meetings, individual and family counseling, and pharmacotherapy with
bupropion (Wellbutrin) and lamotrigine (Lamictal).
Gerry eventually reconciled with his wife and family. He returned to selling cars,
started living modestly, and continued to attend Gamblers Anonymous meetings
regularly. However, he declared emphatically that he always considers himself always
one step away from becoming a “degenerate gambler” again. (Courtesy of Harvey
Roy Greenberg, M.D.)
PSYCHOLOGICAL TESTING AND LABORATORY EXAMINATION
Male patients with gambling disorders have shown abnormalities in platelet MAO
activity. Patients with pathological gambling often display high levels of impulsivity on
neuropsychological tests. German studies have demonstrated increased cortisol levels in
the saliva of gamblers while they gamble, which can account for the euphoria that
occurs during the experience and its addictive potential.
DIFFERENTIAL DIAGNOSIS
Social gambling is distinguished from pathological gambling in that the former occurs
with friends, on special occasions, and with predetermined acceptable and tolerable
losses. Gambling that is symptomatic of a manic episode can usually be distinguished
from pathological gambling by the history of a marked mood change and the loss of
judgment preceding the gambling.
Manic-like mood changes are common in pathological gambling, but they always
follow winning and are usually succeeded by depressive episodes because of subsequent
losses. Persons with antisocial personality disorder may have problems with gambling.
When both disorders are present, both should be diagnosed.
COURSE AND PROGNOSIS
Pathological gambling usually begins in adolescence for men and late in life for women.
The disorder waxes and wanes and tends to be chronic. Four phases are seen in
pathological gambling:
The winning phase, ending with a big win, equal to about a year’s salary, which
hooks patients. Women usually do not have a big win, but use gambling as an escape
from problems.
The progressive-loss phase, in which patients structure their lives around gambling
and then move from being excellent gamblers to being stupid ones who take
considerable risks, cash in securities, borrow money, miss work, and lose jobs.
The desperate phase, with patients frenziedly gambling with large amounts of money,
not paying debts, becoming involved with loan sharks, writing bad checks, and
possibly embezzling.
The hopeless stage of accepting that losses can never be made up, but the gambling
continues because of the associated arousal or excitement. The disorder may take up
to 15 years to reach the last phase, but then, within a year or two, patients have
totally deteriorated.
TREATMENT
Gamblers seldom come forward voluntarily to be treated. Legal difficulties, family
pressures, or other psychiatric complaints bring gamblers to treatment. Gamblers
Anonymous (GA) was founded in Los Angeles in 1957 and modeled on Alcoholics
Anonymous (AA) (Table 20.13-2). It is accessible, at least in large cities, and is an
effective treatment for gambling in some patients. GA is a method of inspirational
group therapy that involves public confession, peer pressure, and the presence of
reformed gamblers (as with sponsors in AA) available to help members resist the
impulse to gamble. The dropout rate from GA is high, however. In some cases,
hospitalization may help by removing patients from their environments. Insightoriented psychotherapy should not be sought until patients have been away from
gambling for 3 months. At this point, patients who are pathological gamblers may
become excellent candidates for this form of psychotherapy. Family therapy is often
valuable. Cognitive-behavioral therapy (e.g., relaxation techniques combined with
visualization of gambling avoidance) has had some success.
Table 20.13-2
Twelve Steps of Gambler’s Anonymous
Psychopharmacological treatment, once largely unsuccessful, now plays a significant
role in the management of pathological gamblers. Effective agents include
antidepressants, notably selective serotonin reuptake inhibitors (SSRIs) and bupropion
(Wellbutrin, Zyban); mood stabilizers, including sustained-release lithium (Eskalith) and
antiepileptics such as topiramate (Topamax); atypical antipsychotics; and opioid agents
such as naltrexone (ReVia). In many patients it is difficult to determine whether an
antidepressant or mood stabilizer alleviates gambling cravings directly or via treatment
of a comorbid condition, particularly depressive or bipolar disorders.
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