DSM-IV Diagnostic Criteria

Substance Dependence

1. 
   

   A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period:

   
   
   
   
   1. 
      

      tolerance

   
   
   
   
   2. 
      

      withdrawal

   
   
   
   
   3. 
      

      the substance is often taken in larger amounts or over a longer period than was intended

   
   
   
   
   4. 
      

      there is a persistent desire or unsuccessful efforts to cut down or control substance use

   
   
   
   
   5. 
      

      a great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects

   
   
   
   
   6. 
      

      important social, occupational, or recreational activities are given up or reduced because of substance use

   
   
   
   
   7. 
      

      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

Substance Abuse

1. 
   

   A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period:

   
   
   
   
   1. 
      

      recurrent substance use resulting in failure to fulfill major role obligations at work, school, or home

   
   
   
   
   2. 
      

      recurrent substance use in situations in which it is physically hazardous

   
   
   
   
   3. 
      

      recurrent substance-related legal problems

   
   
   
   
   4. 
      

      continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance

   
   
2. 
   

   The symptoms have never met the criteria for substance dependence for this class of substance.

Substance Intoxication

1. 
   

   The development of a reversible substance-specific syndrome due to recent ingestion of (or exposure to) a substance.

   
   
2. 
   

   Clinically significant maladaptive behavioral or psychological changes that are due to the effect of the substance on the central nervous system.

   
   
3. 
   

   The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.

Substance Withdrawal

1. 
   

   The development of a substance-specific syndrome due to the cessation of (or reduction in) substance use that has been heavy and prolonged.

   
   
2. 
   

   The substance-specific syndrome causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

   
   
3. 
   

   The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.

(Adapted, with permission, from Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Copyright 1994 American Psychiatric Association.)

This work was supported in part by the National Institute on Alcohol Abuse and Alcoholism (RO1 AA014969) and the National Institute on Drug Abuse (RO1 DA015713 and T32 DA021123).

The substance-related disorders are classified into two categories: (1) substance-use disorders and (2) substance-induced disorders (Table 15–1). The substance-use disorders are (somewhat arbitrarily) dichotomized into substance abuse and substance dependence based on the number of relevant symptoms that the patient exhibits. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) specifies substance-use disorders that result from the self-administration of several different drugs of abuse (Table 15–2).

The specific criteria for diagnosis of substance-use disorders draw heavily on the concept of the dependence syndrome. This important advance in our thinking about these disorders frames the interactions among the pharmacologic actions of the drug, individual psychopathology, and the effects of the environment in a clinically meaningful construct that is generalizable to all drugs of abuse. This concept is derived from the clinical observation that patients may have maladaptive behavior as a result of drug use without the presence of neurophysiologic adaptive changes such as tolerance or withdrawal (also referred to as neuroadaptation). Neuroadaptation is not necessarily dysfunctional if there is no concomitant inappropriate desire to continue the use of the drug (drug seeking). For example, driving while drunk may have devastating consequences, particularly in the sporadically drinking young driver who has not acquired tolerance to ethanol. In another example, the postsurgical patient who has been receiving morphine for pain relief clearly exhibits neuroadaptation but is not likely to develop the dependence syndrome.

Fundamental to the concept of the dependence syndrome is the priority of drug seeking over other behaviors in the maintenance of dysfunctional drug use. Lesser weight is attributed to the presence of tolerance or withdrawal. In general, three (or more) individual symptoms from among the following three symptom clusters need to be part of the clinical presentation for the diagnosis of substance dependence: (1) loss of control (i.e., the substance is taken in larger amounts or over a longer period than intended, or there are unsuccessful efforts to reduce use); (2) salience to the behavioral repertoire (i.e., a great deal of time is spent in substance-related activities at the expense of important social, occupational, or recreational activities that are reduced or given up, or there is continued substance use despite knowledge of having a persistent or recurrent physical or psychological problem likely to have been caused or exacerbated by the substance); and (3) neuroadaptation (i.e., the presence of tolerance or withdrawal).

Diagnosis of a substance-use disorder by the presence of a given number of symptoms provides at best an incomplete picture of various clinically important features of the illness, such as severity, course, and prognosis, as well as indicated treatment for this heterogeneous patient population. The issue of illness severity is addressed in DSM-IV primarily by a distinction between substance abuse and dependence. The importance of diagnostic criteria for drug abuse is evident: They identify the substantial minority of individuals who have a history of maladaptive substance use but do not progress to dependence despite continuing substance abuse and developing certain associated problems. However, the distinction between drug abuse and dependence may not be practical, or possible, if substance-use disorders are considered in terms of continuities rather than categorically. As a result, substance abuse is a residual category, applied only to individuals who do not meet criteria for substance dependence (for the given class of substance) but still experience clinically significant impairment or distress in life functioning as a result of substance use. In order to augment diagnostic sensitivity and also maintain the primacy of drug-seeking behavior, a person can be diagnosed as substance dependent without ever having exhibited tolerance or withdrawal. In DSM-IV, dependence is formally subtyped according to whether or not there is physiologic dependence (i.e., the presence of tolerance or withdrawal). Finally, to better characterize individual patients, certain descriptive terms, or course specifiers, have been added to distinguish among different clinical courses of the dependence syndrome. For example, a dependent patient may be in remission (which may be early or sustained, full or partial), on agonist therapy (e.g., methadone or, more recently, buprenorphine, a mixed μ-opioid receptor agonist–antagonist, that is now used for maintenance treatment much as methadone), or in a controlled environment (e.g., locked hospital ward).

It may be exceedingly difficult to establish whether psychopathology in a given individual who has a substance-use disorder is a consequence of drug use or is due to an additional psychiatric diagnosis. Table 15–3 indicates the broad overlap between substance-induced disorders and other psychiatric syndromes considered in this book. For example, diverse psychiatric signs and symptoms, including those of delirium (see Chapter 14), psychotic disorders (see Chapters 16 and 17), mood disorders (see Chapter 18), anxiety disorders (see Chapter 19), sexual dysfunction (see Chapter 25), and sleep disorders (see Chapter 27), can have their onset during intoxication or withdrawal. Dementia, amnestic disorder, and flashbacks (recurrences of the intoxicating effects of the drug that may occur years after use) associated with hallucinogen use may persist long after the acute effects of intoxication and withdrawal have abated. Accordingly, it is helpful to determine, preferably by longitudinal observation or by history, the timing of the onset of psychopathology with respect to the initiation of drug use, and whether it is still present when drug use has ceased, recognizing that the duration of abstinence can be a determining variable.

Pharmacotherapy of a complicating psychiatric disorder is currently considered appropriate if it is an independent (i.e., a primary) disorder, but not if it is a consequence (i.e., a secondary disorder) of a substance-use disorder. The distinction between whether a complicating psychiatric disorder is primary or secondary to substance dependence is not easily made, particularly if both disorders started early in life or are historically closely intertwined. Nevertheless, the use of medications with dependence liability per se (e.g., benzodiazepines, methylphenidate, barbiturates, anticholinergics) for the treatment of a coexisting psychiatric disorder may be severely detrimental to the patient. Moreover, treatment of a secondary disorder is unlikely to be successful if the co-occurring substance dependence is not adequately addressed.

Integration via a multiaxial diagnostic classification system of the physical, psychological, and social domains of each patient’s clinical presentation is an important feature of DSM-IV. However, this classification approach is not always adequate to describe fully how the dependence syndrome may be modified by diverse factors such as complex drug-use patterns (i.e., more than one drug via different routes of administration), disabilities resulting from drug-use (e.g., mood disorders, brain dysfunction, medical complications), or various personality disorders and the sociocultural context of drug use. Physicians cannot ignore these more difficult issues as they communicate with each other and with other health care professionals or as they serve as legal consultants, perform disability assessments, and help develop health care policy.

Throughout history, members of almost every society have used indigenous psychoactive substances (e.g., opium, stimulants, cannabis, tobacco) for widely accepted medical, religious, or recreational purposes. In more recent times, a wide range of substances (e.g., central nervous system [CNS] depressants and stimulants, hallucinogens, and dissociative anesthetics), synthesized de novo or structurally modified from naturally occurring psychoactive compounds, have also become available for self-administration.

Descriptors of the magnitude and context of psychoactive drug use (e.g., excessive use, abuse, misuse, addiction) represent difficult value judgments. Even if such terms are defined explicitly, they are not likely to be readily generalizable from one society (or group within the society) to another. To demonstrate the arbitrary nature of these terms one needs only to examine the changes in perceptions of drug use in the United States since the 1960s.

Maladaptive patterns of use involve the self-administration of psychoactive agents to alter one’s subjective state and experience of the environment, under inappropriate circumstances or in greater amounts than generally considered acceptable within the social constraints of one’s culture. Medical diagnosis of substance-related disorders requires meaningful diagnostic criteria that are generalizable across cultures and drugs of abuse. Definition of maladaptive patterns of use in terms of their consequences, presumably less influenced by value judgments, has provided the conceptual basis for DSM-IV diagnostic criteria. Accordingly, considerable weight is placed on behavioral factors rather than on purely medical complications of use or physiologic effects. This conceptual advance, theoretically consistent with the biopsychosocial model of health care, is readily amenable to prevention and has important implications for treatment. The diagnostic focus has shifted from the drug per se to the interactions of drug, individual, and societal factors. Such a perspective is quite different from the traditional medical model of considering drug use as merely a bad “habit” until organ damage is diagnosable, or the social model in which even use sufficient to cause physical complications is not considered an illness.

Epidemiology

Surveys conducted by various government agencies at fixed intervals since the 1960s have monitored changes in population attitudes, the prevalences of different types of drug use, health consequences, estimated costs to society, and treatment outcome. Cross-sectional epidemiologic studies are valuable to the clinician, because knowledge of the prevalence of drug-related problems suggests the likelihood with which these problems will be encountered in the patient population. For example, a physician may be assisted in the management of an overdose or other drug-related emergency by knowing “what’s on the street” at that point in time. Longitudinal population studies of cohorts of drug users are particularly informative with respect to understanding antecedents of substance-use disorders, dose-response relationships for consequences of use, and determinants of effective treatment outcome.

Prevalence of Drug Use

Patterns of drug use change over time, and contemporaneous prevalence rates can vary according to the epidemiologic survey quoted. Epidemiologic surveys in the United States documented epidemics of marijuana abuse in the 1960s, heroin in the 1970s, and cocaine in the 1980s. While no single drug captured society’s imagination in the 1990s, opioid dependence has been on the rise, and methamphetamine is perceived to have reached “epidemic” proportions at the onset of the new millennium. Furthermore, epidemiologic studies have documented an upward trend in the usage of all drugs and alcohol during the 1970s, followed by a downward trend in the 1980s; this trend reversed and then stabilized in the 1990s and beyond. Knowledge about the prevalence of drug use is highly predictive of the proportion of the population that will develop abuse or dependence (see below).

Although Americans use alcohol more often than they do any other drug, younger individuals tend to combine alcohol with multiple illicit drugs. Older cohorts (age 35 years and older) frequently use alcohol alone, or with prescribed drugs of abuse. According to the 2004 National Survey on Drug Use and Health (Table 15–4), 121 million Americans (50.3% of the population aged 12 years and older) reported being current drinkers of alcohol (at least one drink in the past month). An estimated 55 million (22.8%) were binge drinkers (5 or more drinks at the same time or within a couple of hours of each other at least once in the past 30 days), and 17 million (6.9%) were heavy drinkers (5 or more drinks on the same occasion on at least 5 different days in the past 30 days). An estimated 70.3 million persons (29.2%) reported use of the other legal drug, tobacco.

An estimated 19.1 million (7.9% of the U.S. population aged 12 or older) used an illicit drug during the month prior to the survey. Marijuana is the most prevalent illicit drug by far, used by 14.6 million in the past month. An estimated 8.2 million people (3.4%) were current users of illicit drugs other than marijuana. Most (6 million) used psychotherapeutic drugs nonmedically. An estimated 4.4 million used pain relievers, 1.6 million used tranquilizers, 1.2 million used stimulants (including 583,000 methamphetamine users), and 300,000 used sedatives. An estimated 2 million persons were current cocaine users (467,000 used crack); hallucinogens were used by 929,000 persons; 166,000 were current heroin users; and 450,000 were current Ecstasy users. National data have consistently shown that substance use, abuse, and dependence are most prevalent among the young (age 18–34 years) and that the highest rates are observed in young men.

Prevalence of Substance-Use Disorders

According to the National Comorbidity Survey, the first survey to be administered in the early 1990s using a structured psychiatric interview (Composite International Diagnostic Interview) to a nationally representative household sample of over 8,000 respondents, the lifetime prevalence rate of a substance-use disorder (except for use of nicotine or caffeine) was 19.5 per 100 persons 18 years and older. Drugs covered by this survey included alcohol, tobacco, sedatives, stimulants, tranquilizers, analgesics, inhalants, marijuana/hashish, cocaine, hallucinogens, heroin, nonmedical use of prescription drugs, and polysubstance use. Alcohol abuse or dependence was identified in 13.2% of the population during their lifetime, and drug abuse or dependence in 8% of the population. According to the 2004 National Survey on Drug Use and Health, an estimated 22.5 million persons (9.4% of persons 12 years and older) were classified as having substance dependence or abuse in the past year (Table 15–5). Of these, 3.4 million were dependent on, or abused, both alcohol and illicit drugs; 3.9 million were dependent on, or abused, only illicit drugs; and 15.2 million were dependent on, or abused, only alcohol. Of the 7.3 million persons classified as being dependent on, or abusing, illicit drugs; 4.5 million were dependent on, or abused, marijuana; 1.6 million were dependent on, or abused, cocaine; and 1.4 million were dependent on, or abused, pain relievers. The majority of other illicit drugs were used in combination with alcohol, marijuana, cocaine, or opioids and by a relatively small proportion of the population who met criteria for substance-use disorder.

Risk of Co-Occurring Psychiatric Diagnoses

According to the National Institute of Mental Health Epidemiologic Catchment Area Survey, in which 20,291 persons representative of the US community and institutional population were interviewed, the odds of having a mental disorder were 2.7 times greater if one also had substance abuse or dependence (excluding nicotine or caffeine) in comparison with no drug-use disorder. Drug-use disorders occurred at higher rates in individuals who had alcohol abuse or dependence (21.5%) than in those who did not (3.7%). Alcohol use disorders were more prevalent among those who met criteria for drug abuse or dependence (47.3%) than among those who did not (11.3%). Specific psychiatric diagnoses, such as major depressive disorder, bipolar affective disorder, schizophrenia, anxiety disorders, and antisocial personality disorder, have been associated with substance-use disorders in epidemiologic studies, leading to theories of common pathogenesis. For example, according to the 2004 National Survey on Drug Use and Health, persons with a major depressive episode (MDE) in the previous year were twice as likely (28.8% vs. 13.8%) as those without MDE to have used an illicit drug in the past year. Similar patterns were observed for specific illicit drugs in the previous year, such as marijuana, cocaine, heroin, hallucinogens, inhalants, and the nonmedically used psychopharmacologic agents. Also, persons with MDE in the past year were 1.3 times as likely (9.2% vs. 6.9%) than those without MDE to be heavy alcohol users. The rate of daily cigarette use was 1.7 times greater in those who had MDE in the last year.

Persons with MDE were more likely than those without MDE to be dependent on, or abuse illicit drugs (9.6% vs. 2.7%) and alcohol (16.8% vs. 7.1%). Among persons with substance dependence or abuse, 18.5% had at least one MDE in the past year compared with 7% among those who did not have substance dependence or abuse.

Such associations suggest that the clinician should have a high index of suspicion for substance-use disorders when dealing with clinical populations diagnosed with mental disorders. The clinician should also be circumspect about prescribing psychoactive medications with dependence liability to these patients.

Etiology

The etiology of substance-use disorders has been conceptualized in terms of an integration of biological, psychological, and social theories. A recent advance has been recognition of shared clinical features, similar biopsychosocial underpinnings, and frequent co-occurrence of substance-use disorders and so-called “behavioral addictions,” such as pathological gambling, problematic hypersexuality, and obesity or other eating disorders.

Individual Vulnerabilities

The major goal of any etiologic theory is to explain why, in the face of widespread availability of drugs and alcohol, certain individuals develop a substance-use disorder, and others do not. This is a gargantuan task because these are complex and multifaceted disorders. Substance abuse and dependence are heterogeneous disorders that represent the final common pathway for a variety of behavioral difficulties in diverse sociocultural contexts. Also, circumstances that lead to these complex and multifaceted disorders differ among individuals. Equally difficult to understand is why in some patients substance-use disorders continue inexorably to death in spite of treatment, whereas in other patients drug use can be decreased or stopped (either spontaneously or with treatment). Therefore, substance-use disorders are perhaps most usefully conceptualized in terms of multiple simultaneous variables interacting over time.

The fact that not all individuals who self-administer psychoactive agents, during given developmental stages or life circumstances, progress to repeated problematic use, has led to the search for factors that determine individual vulnerability. Biological factors that may contribute to the development of substance-use disorders include interindividual differences in (1) susceptibility to acute psychopharmacologic effects of a given drug; (2) metabolism of the drug; (3) cellular adaptation within the CNS to chronic exposure to the drug; (4) predisposing personality characteristics (e.g., sensation seeking, poor impulse control, difficulty delaying gratification, or antisocial traits); and (5) susceptibility to medical and neuropsychiatric complications of chronic drug self-administration. Psychological factors—such as the presence of co-occurring psychopathology (e.g., depression, anxiety, attention-deficit/hyperactivity disorder, psychosis, pathological gambling, eating disorders, or problematic hypersexuality); medical illnesses (e.g., chronic pain, essential tremor); or past or present severe stress (e.g., resulting from crime, battle exposure, sexual trauma, or economic difficulties)—have received considerable attention as potential causes for “self-medication.” The possibility exists that susceptibility to psychological stressors and substance-use disorders may have similar etiologies. For example, some of the etiologic factors that predispose an individual to depression following major losses (e.g., dysregulation of noradrenergic neurotransmission or the hypothalamic-pituitary-adrenal axis) may also contribute to the development of substance-use disorders. Similarly, prefrontal cortical dysfunction manifested by impulsiveness or poor decision making is observed in individuals diagnosed with either pathological gambling or cocaine dependence. Finally, social factors also contribute to the initiation of drug use and progression of substance-use disorders. Such social factors include peer group attitudes toward, and shared expectations of the benefits of, drug use (such as enhanced pleasurable activities with drug use); the availability of competing reinforcers in the form of educational, recreational, and occupational alternatives to substance use; and the availability of drugs during particular developmental stages.

The fact that individuals often use more than one drug simultaneously, or give a history of having used different drugs at different times during their lifetime, has led to an emphasis on the similarities rather than the differences among abused substances with respect to the ontogeny of drug-use behaviors. Further, the stepwise development of different substance-use disorders over time suggests common mechanisms of susceptibility and generalizable diagnostic criteria and treatment strategies. Likewise, the co-occurrence and parallel life courses of substance-use disorders and other out-of-control and self-destructive behaviors, such as pathological gambling, problematic hypersexuality, and over-eating have pointed to shared abnormalities of fundamental brain reward (drive) mechanisms that may be generalized beyond drug self-administration.

Drug-Seeking Behavior

Conceptualization of substance-use disorders in terms of the biopsychosocial model, rather than as simply the physiologic consequences of chronic drug use, has led to recognition of the central role of conditioning and learning in drug dependence. The behavioral perspective provides a framework for understanding the entire spectrum of psychoactive substance use, from its initiation to its progression to compulsive drug use, as well as the acquisition of tolerance and physical dependence; it also explains how co-occurring psychopathology so frequently influences the clinical course of substance-use disorders. Psychopharmacologic processes that initiate, maintain, and regulate drug-seeking behavior include (1) the positive reinforcing and discriminative effects of drugs, (2) the environmental stimuli associated with drug effects (which facilitate drug seeking), and (3) the aversive effects of drugs (which extinguish drug seeking). These processes are modulated by social, environmental, and genetic factors such as the individual’s personal history, the presence of psychopathology (e.g., anxiety, depression, thought disorders), and the individual’s previous exposure to (expectancy of) psychoactive drugs (Figure 15–1). The neural mechanisms and behavioral factors that influence psychoactive drug use are amenable to detailed analysis using drug self-administration models in laboratory animals, in which the neuropharmacology and neuroanatomy of the brain systems that mediate reward can be explored.

Drug Intoxication

Individual factors that affect the quality and magnitude of intoxication also influence drug reinforcement, and ultimately, the development of substance-use disorders. Among these are variables such as initial tolerance, previous experience with the drug, the social context of administration, and presence of disorders that affect CNS responses to the drug or disorders of other organs that determine the brain concentration of the drug. Direct adverse consequences of acute intoxication are predictable from the pharmacologic actions of the drug. For example, CNS depressants have a spectrum of dose-related effects from initial disinhibition at low doses to stupor and coma at higher doses. Similarly, CNS stimulants enhance arousal, attention, and performance at low doses but can lead to psychomotor agitation, psychotic disorganization, and convulsions at higher doses. Often the most serious consequences of these agents are indirect effects, namely, impaired performance or judgment, which can cause automobile or work-related accidents, drug-related violence, or unprotected sexual activity. Finally, the route of drug administration can greatly influence intoxication. For example, both intravenous administration and smoking result in rapid entry of the drug into the brain with intense but relatively short-lived euphoria; for highly reinforcing drugs (e.g., cocaine, opioids), this can result in compulsive, binge-like use. Nasal insufflation, subcutaneous administration (so-called “skin popping”), and oral ingestion result in relatively slower access to the drug’s site of action in the brain, with greater variability in drug bioavailability and less reinforcement.

Neural Mechanisms

Investigation of the neural pathways that mediate the powerful (positive) reinforcing effects of drugs of abuse have implicated dopamine, opioid, glutamate and gamma-amino butyric acid (GABA) systems within a midbrain-forebrain-extrapyramidal reward circuit with its focus in the nucleus accumbens. The connections of the ventral midbrain and forebrain, commonly called the medial forebrain bundle, are a major conduit for hypothalamic afferents and efferents and also support (more than any other brain region) the repeated self-administration of current through electrodes (an intracranial self-stimulation model of addiction). This system modulates, or filters, signals from the limbic system that mediate basic biological drives and motivational variables, convert emotion into motivated action and movement via the extrapyramidal system, and may also be the neuronal substrate for the rewarding effects of drugs of abuse. It has been hypothesized that the mesocorticolimbic dopamine system may be critical in motor arousal associated with anticipation of reward, and that all addictive drugs have a psychostimulant (dopaminergic) action as a common underlying mechanism that contributes to reinforcement. Therefore, drugs of abuse activate neural pathways evolved to guide an organism through the challenges of the environment by reinforcing behavior essential for the survival of the species. If drugs of abuse are repeatedly administered, these reward circuits may cease to shape survival behavior effectively.

Behavioral Mechanisms

The effects of drugs that mediate their positive reinforcing influence are desirable changes in mood (euphoria), alleviation of negative affective states (e.g., anxiety, depression), functional enhancement (e.g., improved psychomotor or cognitive performance), and alleviation of withdrawal. It is difficult to understand why certain psychoactive drugs with profound aversive effects can nonetheless maintain drug-seeking behavior and have dependence liability. Aversive effects of drugs counteract the tendency toward self-administration and may limit drug use if they result in dose-dependent toxicity. For example, initial exposure to nicotine in the form of cigarettes often results in distressing symptoms, such as coughing, nausea, and lightheadedness, which may terminate smoking. Similarly, severe gastritis in the chronic alcoholic patient may result in attempts to cut down drinking or limit continued alcohol ingestion. It is now recognized that the stimulus properties of most drugs of abuse, a major determinant of drug-seeking behavior, are complex and multifaceted. Specifically, their pharmacologic profiles include both positive reinforcing and aversive components, and their effects are modified readily by associated environmental stimuli and individual differences among drug users.

If a drug is repeatedly administered under given circumstances (situation, time, place), environmental stimuli can become associated with effects of the drug by means of classical (Pavlovian) conditioning. Subsequently, the circumstances under which the drug was administered (without actual presentation of the drug) comprise certain environmental (conditioned) stimuli that can modify drug-seeking behavior, subjective state, or psychophysiologic responses (conditioned reinforcement). For example, patients who have abstained from intravenous heroin for many years can experience a desire to use heroin when they return to the location where they previously used or when they view a film that portrays others who are injecting drugs intravenously. Using positron emission tomography (PET), researchers have shown that in dependent patients, dopaminergic activation accompanies the presentation of relevant cues from the environment or the anticipation of drug (without its administration). Moreover, similar patterns of brain activation are demonstrable using functional magnetic resonance imaging (fMRI) when a subject is presented cues related to highly rewarding behaviors that do not involve drug self-administration, such as gambling, sexual activity, and food. The importance of conditioned stimuli in the response to drugs is also demonstrated readily in laboratory animals by tolerance after a drug is tested in an environment in which it was administered previously that is greater than in a distinctly different environment.

Neuroadaptation

Neuroadaptation refers to the neuronal changes and consequent clinical signs and symptoms that result from repeated drug administration independent of drug-seeking behavior or use-related organ damage. It encompasses the biological substrata of tolerance and physical (as opposed to psychological) dependence.

Tolerance

After repeated exposure to many psychopharmacologic agents, individuals require a larger dose to produce intoxication of the magnitude that was experienced when the drug was first administered. Conversely, a smaller degree of intoxication results from doses of the drug that were used initially. This phenomenon, called tolerance, is a pharmacologic characteristic shared by many of the substances of abuse considered in DSM-IV (particularly the CNS depressants and the opioids). Tolerance allows and may encourage progressively greater doses to be self-administered. (After repeated exposure to CNS stimulants, reverse tolerance, or a greater pharmacologic effect, may be observed.) Tolerance is an adaptive physiologic response of the intact organism that opposes the pharmacologic effects of the drug. The mechanistic underpinnings reside in molecular changes at the cellular level and in interactions between the organ systems of the body. The components of tolerance include (1) increased capacity for clearance of a drug by metabolizing enzymes in the liver (pharmacokinetic or metabolic tolerance), (2) reduced response from the same drug concentration (functional or pharmacodynamic tolerance), and (3) accommodation to drug effects through learning (behavioral or learned tolerance). Tolerance to one CNS depressant usually results in some cross-tolerance to other (sometimes chemically unrelated) CNS depressants. Tolerance accelerates dose-related complications of drug use.

Acquired tolerance should be distinguished from sensitivity to a given drug on first administration and from acute tolerance that develops over the course of a single exposure to the drug. Differences in the population in initial or acute tolerance to a given drug are innate characteristics of the CNS that may influence individual vulnerability to the development of psychoactive substance-use disorders.

Dependence

Traditionally, dependence refers to the neuronal changes that develop after repeated exposure to a given agent, the clinical syndrome characterized by out-of-control drug use, and the serious biopsychosocial consequences that accompany these neuronal changes. At present, dependence can be defined only indirectly in terms of (1) the presence of tolerance or the emergence of a withdrawal syndrome (immediate and protracted) upon drug discontinuation (physical dependence) and (2) the craving or drug-seeking behavior manifested as a result of conditioned stimuli (psychological dependence). The dependence syndrome represents the elements of psychological dependence, including drug seeking and psychosocial consequences of drug use. Physical dependence usually develops in concert with tolerance, and controversy remains over whether physical dependence and tolerance are simply different manifestations of the same neuronal changes. The reacquisition of both tolerance and physical dependence are accelerated following repeated cycles of drug administration and withdrawal, suggesting certain similarities between these phenomena and learning and memory. Furthermore, the reinforcing and aversive affects of drugs may differ considerably at different stages in the course of a substance-use disorder (see Figure 15–1).

Withdrawal

Upon discontinuation of chronic administration of many psychoactive agents (or administration of a specific antagonist), a withdrawal (abstinence) syndrome emerges as drug concentrations (or receptor occupancy) at the pharmacologic sites of action decline. This syndrome is characterized by a spectrum of signs and symptoms that are generally opposite to those of intoxication and whose severity is related to the cumulative dose (dosage and duration of administration). For example, withdrawal from CNS depressants results in CNS hyper excitability, whereas withdrawal from psychostimulants causes CNS depression. For most drugs of abuse, the withdrawal syndrome also involves homeostatic responses. These represent reversal of the neuroadaptive changes that occurred with long-term drug administration, resulting in significant activation of the autonomic nervous system.

Cellular & Molecular Mechanisms of Neuroadaptation

Advances in neuroscience, such as the development of specific receptor antagonists, electrophysiological and brain imaging techniques, and molecular methods to measure subtle cellular alterations, have enhanced our fundamental understanding of neuroadaptation. Neuroadaptation can be conceptualized not only in terms of the intact organism (of particular relevance to understanding the clinical signs and symptoms of withdrawal), but also at the level of neuronal signal transduction, which can be studied in vitro. Changes in synaptic membrane composition, receptor function, and postreceptor intracellular events have all been proposed as the basis of neuroadaptation to psychoactive drugs of abuse. For example, acute alcohol exposure fluidizes cell membranes, but chronic alcohol exposure results in alterations in the lipid composition that render synaptic membranes more rigid. The inhibition by cocaine of dopamine reuptake leads to increased intrasynaptic dopamine, subsequent depletion of presynaptic dopamine due to reduced synthesis of the neurotransmitter, and eventual upregulation (enhanced sensitivity) of postsynaptic dopamine receptors. Finally, in rats, chronic morphine administration increases G proteins, cyclic adenosine monophosphate–dependent protein kinase, and the phosphorylation of a number of proteins, including transcription factors. Emerging evidence points to similar functional changes on reward pathways following administration of many of the drugs of abuse, as well as natural reinforcers. Such a common pathway of responses might be akin to the molecular-level alterations that occur during learning and memory. Keys to molecular changes during acute drug administration and during neuroadaptation have clear implications for the pharmacotherapy of dependence and withdrawal.

Genetics

The clinical features and course of alcohol dependence have been studied more extensively than have those of other substance-use disorders. Alcohol dependence is a heuristically useful paradigm for understanding the genetic factors that contribute to the development of most substance-use disorders. In fact, recent studies show shared genetic factors associated with alcohol and other drug-use disorders. As discussed earlier in this chapter, individual vulnerabilities to substance-use disorders span biological, psychological, and social domains. These domains are tightly interrelated and can influence one another, such that it may be difficult to unravel the role(s) of single variables. Furthermore, substance abuse or dependence in family members disrupts family life in countless ways, thereby affecting developmental processes in children within the family. It is not surprising, therefore, that higher than normal rates of alcohol or drug dependence, as well as of other forms of psychopathology, exist among children of these families. In addition to these environmental factors, genetic factors also play a role in the familial predisposition to substance-use disorders. However, it is recognized that interactions of the genetic and environmental factors associated with drug-use disorders may be more important than either of these factors alone.

Inheritance of Alcohol Dependence

Findings from twin and adoption studies demonstrate the relative contributions of genetic and environmental factors in predisposition to alcohol dependence. For example, the concordance rate for alcohol dependence is substantially higher in monozygotic (0.70) than dizygotic (0.33) twins, whereas concordance rates are no different for less severe forms of the disorder, such as alcohol abuse (0.8 for both monozygotic and dizygotic twins). Adoption studies show that adopted-away men with alcoholic biological parents have an increased likelihood of developing alcoholism regardless of whether they are raised in an alcoholic or nonalcoholic environment. In general, the severity of parental alcoholism tends to influence the prevalence of alcoholism in adopted-away sons; patients with the most severe alcoholism have the highest rates of alcohol dependence in their offspring. These studies suggest that the relative contributions of environmental and genetic factors in development of alcoholism may vary with the severity or type of alcohol dependence.

Heterogeneity of Alcohol Dependence

As discussed earlier in this chapter, groups of alcohol-dependent patients are heterogeneous. The challenge in genetic studies of alcoholism has been to identify homogenous subgroups of alcohol-dependent patients. Clearly defined phenotypes in patients (and their families) could then be studied in depth to identify predictors of etiology, longitudinal course, and response to treatment. One heuristically useful classification is based predominantly on age at onset of alcohol dependence: onset after age 25 (type 1) and onset before age 25 (type 2). Reliably different clusters of alcohol-related problems and personality traits tend to occur with these two subtypes of alcohol dependence. In general, patients with type 2 alcoholism are characterized by thrill seeking, impulsiveness, and aggressiveness, whereas those with type 1 alcoholism have a greater tendency to become anxious and depressed as a result of their drinking. Type 2 alcoholism tends to be more recalcitrant to treatment than is type 1 alcoholism.

Both genetic predisposition and an alcoholic rearing environment were required for adopted-away sons of fathers with type 1 alcoholism to express type 1 alcoholism. In contrast, adopted-away sons of fathers with type 2 alcoholism were significantly more likely to manifest this type of alcohol dependence than were the offspring of fathers without type 2 alcoholism, whether or not they were raised in an alcoholic family. This observation indicates that the genetic loading for alcohol dependence is influenced profoundly by the environment in the case of late-onset alcohol dependence, whereas environmental background is relatively less important for early-onset alcohol dependence.

Women & Addiction

There are distinct differences between the genders in the inheritance, clinical presentation, and longitudinal course of alcohol dependence. It is particularly important to understand alcohol use disorders in women because of the adverse effects of drinking on the developing fetus, and the disruptive effects of alcohol use or dependence on the mother–child relationship. Both of these consequences of alcohol consumption in women can perpetuate the transmission of alcohol use and other psychiatric disorders from one generation to the next via nongenetic means.

Women have lower rates of alcohol dependence compared to men, although these rates are rising at a disquieting pace. Lower rates of alcohol dependence result in part from the smaller amounts of alcohol consumed by women in general, for a number of psychosocial and biological reasons. Even though women start drinking later than men, they tend to develop, at about the same age as men, more serious physical complications. These observations suggest greater intrinsic toxicity of ethanol to the liver, brain, and possibly other organ systems of women compared to men. Established gender-related differences in predisposition to co-occurring psychopathology (e.g., depression and somatic anxiety) may complicate and exacerbate alcohol dependence. Daughters of fathers with type 1 alcoholism are at increased risk for alcoholism but not for other psychopathology; daughters of fathers with type 2 alcoholism are at higher risk only for somatization disorder.

Genetic Factors in Development of Alcoholism

Although genetic studies suggest that genetic factors are important contributors to the development of alcohol dependence, the mechanisms involved are only now beginning to be elucidated. This is an exciting area of research, but its clinical relevance is not yet apparent. Because there is likely a complex cascade of events between the genetic underpinnings of alcohol dependence and the eventual manifestation of symptoms, this clinical diagnosis is probably not the best phenotype for use in genetic analyses. A preferable phenotype for genetic analyses might be an intermediary measure of the neuropsychiatric functioning involved in the pathway between genotype and the outcome of interest (endophenotype). For example, it has been suggested that children of alcoholic fathers are less sensitive to the intoxicating effects of ethanol than are children of nonalcoholic fathers. Presumably, these children would have to drink more than would children of nonalcoholic fathers in order to become intoxicated and, thus, be more likely to become alcohol dependent. The abilities of researchers to match subjects retrospectively in terms of lifetime exposure to, and experience with, alcohol are important limitations of these studies. Such limitations can be overcome only by carefully conducted longitudinal investigations beginning in childhood. Early notions that differences in innate tolerance to ethanol or susceptibility to alcohol dependence were based on differences in ethanol metabolism have not been firmly established. More recently, researchers have focused on molecular underpinnings of interindividual differences in, for example, the GABAA receptor genotype or brain biogenic amine metabolism as predisposing to development of alcohol dependence. Specifically, considerable preclinical and human data implicate low brain serotonergic activity in stimulating alcohol consumption and in producing the aggressive and impulsive behavior often associated with type 2 alcoholism. In addition, an impaired ability to allocate significance to targeted stimuli, as manifested by reduced amplitude of the late positive component of event-related electroencephalographic (EEG) potential, has been identified in children of fathers with type 2 alcoholism, and is considered a genetic factor predisposing to alcohol dependence. Early onset alcoholics may be more prone to develop brain damage as a result of alcohol consumption. They may be cognitively impaired prior to beginning drinking, especially with respect to attention and motor control. This line of reasoning is supported by relationships found between adult alcohol dependence and early delays in motor development, suggesting that fronto-cerebellar deficits play a causal role.

Inheritance of Substance-Use Disorders Other Than Alcohol Dependence

It is unknown whether the genetic mechanisms that predispose individuals to alcohol dependence also influence the development of other substance-use disorders. Common causality is suggested (though difficult to prove) because many (particularly younger) individuals tend to combine alcohol and other drugs of abuse, often indiscriminately.

The twin and adoption studies described earlier in this chapter provide guidelines for how to study this question in patients with drug abuse or dependence. For example, in one adoption study of genetic and environmental factors in drug abuse, drug abuse in adult adoptees was associated in equivalent proportions with (1) antisocial personality in the adoptees, related to a biological background of antisocial personality; (2) no antisocial personality in the adoptees but with a biological background of alcoholism; and (3) neither antisocial personality nor alcoholism in either the adoptee or the biological background but psychosocial factors such as divorce and psychiatric illness in the adopting family environment. Such studies show that interactions between genetic and environmental factors are as important in the development of other substance-use disorders as they are for alcohol dependence. A shared underlying mechanism seems most likely to involve endophenotypes related to attention, impulse control, executive functioning, related abnormalities of brain functioning, or the presence of, or vulnerability to, depression, anxiety, or related psychopathology.