CHAPTER 23

Substance-Related and Addictive Disorders

Thomas R. Kosten, M.D.

Thomas F. Newton, M.D.

Richard De La Garza II, Ph.D.

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

Humans have been using botanical and chemical substances to achieve altered states of consciousness for thousands of years. A majority of people in the world use at least one psychoactive substance, and many of these substances are ubiquitous within a culture (e.g., caffeine, tobacco). Most individuals engage in use without encountering difficulties, although a small percentage of them develop substance-related disorders that can lead to considerable burden and cost on many levels. For example, tobacco and alcohol use disorders together significantly contribute to the development of serious diseases (e.g., lung cancer, liver cancer) worldwide. In the United States, tobacco use in particular is the number one preventable cause of death.

In this chapter we present an overview of substance-related disorders. DSM-5

(American Psychiatric Association 2013) further divides these disorders into substance use and substance-induced disorders, focusing primarily on 10 drug classes: 1) alcohol; 2) caffeine; 3) cannabis; 4) hallucinogens; 5) inhalants; 6) opioids; 7) sedatives, hypnotics, and anxiolytics; 8) stimulants (cocaine and amphetamine-like drugs); 9) tobacco; and 10) other (or unknown) substances (Table 23-1). Unique to DSM-5 is the addition of gambling disorder as a non-substance-related disorder. In-depth information specific to each substance-related and addictive disorder is provided in this chapter.

Classification Systems

DSM-5 defines disorders related to nine classes of substances that include commonly recognized drugs of abuse. Most of these drugs can lead to substance use disorders as well as substance-induced disorders. Substance-induced disorders are categorized in DSM-5 as intoxication, withdrawal, and other substance/medication-induced mental disorders. The World Health Organization's (2011b) International Statistical Classification of Diseases and Related Health Problems, 10th Revision, 2010 Edition (ICD-10 Version: 2010) has similar designations but also includes harmful use. ICD-10 additionally includes a high-/low-risk system for alcohol that focuses exclusively on quantity and frequency criteria. Notably, the word addiction is not part of DSM-5. The DSM-5 diagnostic criteria for substance intoxication require the presence of "clinically significant" problematic behavioral or psychological changes that develop after ingestion of a substance:

The most common changes in intoxication involve disturbances of perception, wakefulness, attention, thinking, judgment, psychomotor behavior, and interpersonal behavior. Short-term, or "acute," intoxications may have different signs and symptoms than sustained, or "chronic," intoxications. For example, moderate cocaine doses may initially produce gregariousness, but social withdrawal may develop if such doses are frequently repeated over days or weeks. (American Psychiatric Association 2013, pp. 485-486)

Note. LSD=lysergic acid diethylamide; MDMA=3,4-methylenedioxymethamphetamine (Ecstasy).

Approach to the Patient

A patient with a substance use disorder may present with complaints of mood problems, anxiety, sleep difficulties, or symptoms of another psychiatric disorder. Screening with instruments such as the CAGE (Mayfield et al. 1974), the Michigan Alcohol Screening Test (MAST; Selzer 1971), or the Alcohol Use Disorders Identification Test (AUDIT; Babor et al. 2001) is essential, and urine toxicologies can be invaluable to unmask substance use disorders (Work Group on Substance Use Disorders 2010). Societal stigma and the illegality of some substances cause individuals to hide their use. Questions must be asked with nonjudgmental empathy and caring professional interest rather than confrontational challenging. The basic areas of inquiry are listed in Table 23-2. Information from collateral sources, with the patient's consent, and repeated assessments are needed for accurate treatment recommendations. A high degree of clinical vigilance should be maintained for intoxication and withdrawal when treating patients in inpatient general medical or psychiatric settings. The emergence of agitation, confusion, or delirium due to an unanticipated withdrawal syndrome is not rare.

Treatment

General Principles

Intoxication and Withdrawal

Severe intoxications can be life threatening and require emergent general medical care. Two approaches can prevent acute withdrawal. One method is to substitute a cross-tolerant, less harmful, and usually longer-acting medication for the abused drug, such as substituting methadone for heroin or diazepam for alcohol. The dosage is adjusted until withdrawal symptoms are minimized, and then the medication is gradually tapered off. The second approach is to use a non-cross-tolerant medication to reduce withdrawal symptoms, such as using clonidine for opioid withdrawal or carbamazepine for alcohol withdrawal.

Source. Adapted from Work Group on Substance Use Disorders 2010.

Substance-Related Disorders

Substance-related disorders encompass substance use disorders and substance-induced disorders. The treatment of substance use disorders depends on the patient's acceptance of or motivation for treatment, the problem severity, and the specific drug abused because specific relapse-prevention agents are available for some drugs (e.g., naltrexone for alcohol or opiates, methadone or buprenorphine for opiates, varenicline or nicotine replacement for tobacco). In most situations, treatment is to some extent voluntary or at least selected as an option by the patient; however, patients can be mandated to treatment by the legal system, and they may have better outcomes than similar groups of voluntary patients. The Patient Placement Criteria algorithm developed by the American Society of Addiction Medicine may be used to assign a patient to one of five levels (or sublevels) of care based on six assessment dimensions (Table 23-3) (Mee-Lee et al. 2012). Patients who are correctly matched to a treatment based on this algorithm have shown better outcomes than mismatched patients. Spontaneous recovery without formal treatment, such as through participation in self-help groups, also occurs for about 20% of individuals with substance use disorders.

Psychotherapies

Behavioral interventions are central to recovery in all substance use disorder treatments. The most prevalent and widely used interventions are those of the mutual self-help groups that use a twelve-step program such as that originated by Alcoholics Anonymous. A number of professional psychotherapies are effective, but prognostically matching exactly which type of psychotherapy is best for which individual patients has not been possible.

Outcomes

Outcomes in substance use disorder treatment are not simply abstinence; instead, treatment may focus sequentially on intermediate objectives, such as moving to greater levels of motivation when starting coercive treatments, decreasing psychiatric hospitalizations, and attaining more drug-free urine tests. Population-based public health outcomes include cost savings, decreased incarcerations, and increased productivity from employment. Economically, a large number of studies, using different methods and conducted at different times, have shown that $1 spent on treatment saves between $4 and $7 in direct, indirect, or combined costs. As summarized by McLellan et al. (2000), "1-year postdischarge follow-up studies [after substance abuse treatment show that] 40% to 60% of discharged patients are continuously abstinent, although an additional 15% to 30% have not resumed dependent use during this period" (p. 1693).

Neurobiology

Chronic substance use eventually results in structural and functional brain abnormalities that may result in a withdrawal syndrome upon ceasing drug intake. Another component of substance use disorders is intense drug craving that is associated with relapse. The neurobiology of drug withdrawal and drug craving is mediated by different yet overlapping brain circuits. Many abnormalities associated with substance use disorders resolve within days or weeks after the substance use stops. However, long-lasting brain structural changes may relate to persistent preoccupation with and relapse to drug use. Structural changes lead to abnormal brain function that may be amplified by environmental effects—for example, stress, social context of initial drug use, and psychological conditioning. Genetics also plays a significant role due to aberrant brain pathways that were abnormal even before the first dose of a particular drug was taken. These pathways predispose an individual to develop a substance use disorder. Such abnormalities can produce craving that leads to relapse months or years after the individual is no longer dependent.

*Within each general level of care are a number of more refined sublevels.

Source. Mee-Lee et al. 2012.

As shown in Table 23-4, all drugs of abuse increase the neurotransmitter dopamine (DA) to supraphysiological levels within specific brain reward circuitry. DA then binds to unique dopaminergic receptor proteins on the surface of pre-and postsynaptic neurons (Figure 23-1). An example of this process is the opiate heroin, which binds to μ opioid receptors, which are on the surfaces of opiate-sensitive neurons and have their effects by inhibiting the cyclic adenosine monophosphate (cAMP) second messenger system. Inhibition occurs through a G protein-mediated coupling, leading to a series of changes in phosphorylation for a wide range of intraneuronal proteins. The ability of heroin to bind with μ opioid receptors imitates the action of endogenous opioids such as (3-endorphin with these same receptors and triggers the same biochemical brain processes that are associated with normally induced positive subjective feelings from normal activities that promote pleasure, such as eating and sexual activity. Opioids like oxycodone or methadone are prescribed therapeutically to relieve pain, but when these exogenous opioids activate the reward processes in the absence of significant pain, they can usurp normal brain reward circuitry and motivate repeated use of the drug simply for pleasure.

The mesocorticolimbic (midbrain and cortex) reward system consists of brain circuits activated by all abused drugs. This system generates signals in a part of the brain called the ventral tegmental area (VTA) that result in DA release in another part of the brain, the nucleus accumbens (NAc), where VTA neurons project. This release of DA into the NAc is associated with positive subjective drug effects (Volkow et al. 2010). Other areas of the brain play important roles in continuing drug use. A lasting record or memory is created that associates these good feelings with the circumstances and environment in which they occur (hippocampus). These memories, called "conditioned associations," utilize brain circuitry that also mediates drug craving (amygdala) when the abuser reencounters those persons, places, or things (orbitofrontal cortex) and is then driven to make poor decisions and seek out more drugs in spite of many obstacles (prefrontal cortex) (Goldstein and Volkow 2011).

Note. DA=dopamine; DAT=dopamine transporter; GABA=γ-aminobutyric acid; MAO=monoamine oxidase; nAChR=nicotinic acetylcholine receptor; NE=norepinephrine; NET=norepinephrine transporter; NMDA=N-methyl-D-aspartate; SERT=serotonin transporter; VMAT2=vesicular monoamine transporter 2; VTA=ventral tegmental area.

Other abused drugs activate this same brain circuitry, but via different mechanisms and by stimulating or inhibiting different neurons in these circuits. For example, opioids and cannabinoids (see Figure 23-1) can inhibit activity in the NAc directly, whereas stimulants such as cocaine, methamphetamine (METH), and amphetamine (AMPH) act indirectly by binding to various DA transporters and either inhibiting the reuptake of DA back into the VTA neurons for recycling (cocaine) or actively pumping DA out of the VTA neurons (METH, AMPH).

Figure 23-1. Substance use disorders: mechanisms of action.

Note. Ca²⁺=calcium ion; CB₁ = cannabinoid receptors; Cl^-=chloride ion; DA=dopamine; DAT=dopamine transporter; GABA=γ-aminobutyric acid; METH/AMPH=methamphetamine/amphetamine; NMDA=N-methyl-D-aspartate; TH=tyrosine hydroxylase; VMAT=vesicular monoamine transporter.

Potent drug effects on brain reward circuitry that produce positive subjective effects are the primary reason that some people continue to take drugs, particularly in the early stages of abuse. However, the continued drive and compulsion to use drugs build over time and extend beyond simple pleasure seeking. This increased compulsion is related to enhanced incentive to procure and take drugs. Chronic drug administration eventually leads to abnormal synaptic plasticity, which is responsible for tolerance, dependence, and withdrawal upon cessation of drug use. Reversal or normalization of aberrant neurotransmission is an essential goal of pharmacotherapies.

From a clinical standpoint, withdrawal can be one of the most powerful factors driving dependence and addictive behaviors. Consistent with the concept of drug-induced neuroadaptations, repeated exposure to escalating dosages of most drugs alters the brain so that it functions more or less normally when drugs are present but abnormally when they are not. Two clinically important observations that are a consequence of these neuroadaptive effects include drug tolerance (the need to take higher and higher dosages of drugs to achieve the same effect) and drug dependence (susceptibility to withdrawal symptoms). The neurobiological substrates responsible for tolerance and withdrawal symptoms overlap because withdrawal symptoms occur only in patients who have developed tolerance.

Tolerance occurs because the brain cells that have receptors or transporters on them gradually become less responsive to the stimulation by the exogenous substances. For example, more heroin or morphine is needed to inhibit cAMP and downstream second messenger systems within the VTA-NAc circuit as well as to stimulate VTA neurons to release the same amount of DA in NAc terminals. Therefore, more opioid is needed to produce pleasurable subjective effects comparable to those produced in previous drug-taking episodes. The reduced response is in part due to alterations in the intracellular second messenger pathways involving the transcription factor CREB (cAMP response element binding protein). Drug-induced changes in CREB influence gene expression of various proteins. Altered gene expression results not only in long-term structural changes in genes responsible for neuron integrity (brain-derived neurotrophic factor [BDNF], glia-derived neurotrophic factor [GDNF]) and sensitivity, but also in the amounts of receptors and transporters. For example, chronic cocaine-induced inhibition of the DA transporter (DAT) is associated with decreased DA D₂/D₃ receptors, whereas the DAT, norepinephrine transporter (NET), and serotonin transporter (SERT) are increased, presumably to compensate for cocaine's effects. These changes, along with changes in other proteins and neurotransmitters associated with tolerance, may be considered an attempt by the brain to attain relative homeostasis in response to drug-induced disruption of normal neurotransmission. Tolerance to alcohol may be due to a more complex series of yet to be determined neurobiological changes at the neuronal and molecular levels involving γ-aminobutyric acid (GABA), opioid, DA, and other neurochemical systems, including the excitatory amino acid neurotransmitters such as glutamate and its multiplicity of receptor subtypes (Sulzer 2011). Tolerance to cannabinoids probably has a similar mechanism to opioids, because the cannabinoid CB₁ receptor is also coupled to inhibitory G proteins that decrease cAMP levels and is associated with low D₂/D₃ receptor numbers. Chronic cannabinoid use, in contrast to use of cocaine but similar to use of most other addictive drugs, is associated with decreased DAT levels. Neurobiological mechanisms that mediate tolerance following chronic administration of a hallucinogen such as lysergic acid diethylamide (LSD) are complex and presently unknown but probably involve changes in serotonin type 2 (5-HT₂) receptors linked to the phosphatidylinositol phosphate second messenger system.

Limited or occasional drug use may transition to active daily, even compulsive, drug administration characterized by withdrawal symptoms and intense craving. Physical and/or psychological withdrawal occurs upon stopping drug intake and further contributes to relapse. Neuroplastic changes occur at each stage in the development of addiction. These changes recruit and strengthen connections between specific brain areas while reducing the influence of other areas. Long-lasting neuroadaptive brain changes are related to adverse consequences that are the hallmarks of addiction. The transition to addiction is also greatly influenced by an individual's genetic makeup interacting with environmental factors (stress in particular). Several models have been generated to help explain how occasional drug use produces changes in the brain that may lead to drug addiction. In reality, the process of addiction probably involves many different factors yet to be recognized or explained.

Long-term pharmacotherapies for opioid dependence include methadone, naltrexone, and buprenorphine, which can counteract or reverse the abnormalities underlying dependence and addiction. These agents are particularly informative because they are an agonist, antagonist, and partial agonist, respectively. Methadone tends to normalize many aspects of the hormonal disruptions found in addicted individuals. For example, it moderates the exaggerated cortisol stress response that increases the danger of relapse in stressful situations. Naltrexone occupies μ opioid receptors in the brain with a 100-fold higher affinity than agonists such as methadone or heroin so that addictive opioids cannot link up with them and stimulate the brain's reward system. Naltrexone also does not stimulate these μ receptors, but it appears to increase the number of available μ opiate receptors, which may help to renormalize the imbalance between the receptors and G protein coupling to cAMP. At low dosages buprenorphine has effects like methadone, but at high dosages it behaves like naltrexone, blocking the receptors so strongly that it can precipitate withdrawal in highly dependent patients. Buprenorphine has less overdose potential than methadone, because it blocks other opioids and even itself as the dosage increases.

Pharmacological interventions for addiction are highly effective for opiates, and we have illustrated different approaches using an agonist, antagonist, and partial agonist. Clinician awareness of the neurobiological basis of drug dependence, as well as information sharing with patients, can help provide insight into patient behaviors and problems and clarify the rationale for treatment methods and goals.

Alcohol-Related Disorders

Epidemiology

According to results from the 2010 National Survey on Drug Use and Health, 131.3 million people ages 12 years and older reported being current alcohol drinkers. An estimated 58.6 million participated in binge drinking (five or more drinks on one occasion at least once in the previous 30 days), and nearly 17 million reported heavy drinking (five or more drinks on the same occasion on 5 or more of the previous 30 days) (Substance Abuse and Mental Health Services Administration 2010). According to the Centers for Disease Control and Prevention (2012), alcohol drinking is the third leading cause of preventable death in the United States. The latest available estimates show that lost productivity, health care, and criminal justice costs linked to excessive alcohol drinking approached $223 billion in 2006 (Bouchery et al. 2011). The DSM-5 criteria for alcohol use disorder are presented in Box 23-1.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Intoxication

Acute alcohol intoxication is a potentially harmful condition that ensues following ingestion of a significant amount of alcohol (Box 23-2). Numerous factors such as body weight, amount and type of alcoholic beverage, time in which the alcohol was consumed, individual tolerance, metabolism, and genetic makeup all influence the extent of alcohol intoxication. Table 23-5 presents clinical symptoms associated with blood alcohol concentration (BAC) in individuals without alcohol use disorder. Individuals with alcohol use disorder will generally show tolerance to these effects. Nevertheless, death secondary to an acute high dose of alcohol (BAC >400 mg/dL) is often due to respiratory depression.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Source. Vonghia et al. 2008.

Withdrawal

Clinically significant withdrawal symptoms generally occur about 8 hours following cessation of heavy or prolonged drinking. Symptoms tend to reach maximal intensity on day 2 when BAC decreases but resolve considerably by days 4-5. The DSM-5 diagnostic criteria for alcohol withdrawal (Box 23-3) list commonly seen withdrawal symptoms. These symptoms are mediated in part by reduced central GABA and increased glutamatergic neurotransmission. Less than 5% of individuals with alcohol use disorder undergoing severe withdrawal exhibit seizures that require emergent hospital care. Roughly the same percentage of individuals experience delirium tremens (DT), characterized by agitation, auditory and visual hallucinations, and frank disorientation (Schuckit 2009). The intensity of alcohol withdrawal can be closely monitored using the Clinical Institute Withdrawal Assessment for Alcohol Scale—Revised (CIWA-Ar; Sullivan et al. 1989) (Figure 23-2).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Figure 23-2. Clinical Institute Withdrawal Assessment for Alcohol Scale—Revised (CIWA-Ar).

Source Reference. Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM: "Assessment of Alcohol Withdrawal: The Revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar)." British journal of Addiction 84:1353-1357, 1989.

Web Source. U.S. Department of Veterans Affairs Center for Health Care Evaluation (CHCE) Web Site (www.chce.research.va.gov/apps/PAWS/content/downloads.htm).

Diagnosis

A number of useful, quickly administered questionnaires have been designed to screen for heavy drinking and alcohol use disorders in clinical settings. The sensitivity and specificity of these screening tools vary (Table 23-6), so these questionnaires should be considered as initial assessments only. Positive responses on the CAGE and TWEAK questionnaire screens (Table 23-7), for example, should prompt further assessment with more extensive screens such as the AUDIT (Figure 23-3).

Laboratory tests that assess biomarkers known to reflect alcohol consumption can augment data from questionnaire screens. Table 23-8 lists biomarkers and their biochemical parameters that have proven useful in diagnosing and monitoring alcohol use disorders. γ-Glutamyltransferase (GGT) is a membrane-bound liver enzyme important in the synthesis and degradation of glutathione in intracellular detoxification and is elevated in heavy drinkers. Percent carbohydrate-deficient transferrin (%CDT) is the percentage of circulating glycoprotein transferrin that is carbohydrate deficient. Serum %CDT is considered to be more useful in detecting heavy drinking because levels correlate with increases in alcohol consumption, especially in patients with liver disease. Utilizing both biomarkers, %CDT and GGT, enhances the sensitivity (90%) in detecting heavy drinkers compared with use of either one alone (%CDT, 63%; GGT, 58%) (Hietala et al. 2006).

Circle the number that comes closest to the patient's answer.

Figure 23-3. Alcohol Use Disorders Identification Test (AUDIT).

Source. Reprinted from Babor TF, Higgins-Biddle JC, Saunders J, et al.: AUDIT, the Alcohol Use Disorders Identification Test, 2nd Edition. Geneva, Switzerland, World Health Organization, 2001. Available at: http://whqlibdoc.who.int/hq/2001/WHO_MSD_MSB_01.6a.pdf Accessed July 30, 2006. May be reproduced without permission for noncommercial purposes.

Source. Niemelä 2007; Schuckit 2009.

Treatment

Acute Withdrawal

Signs and symptoms of acute alcohol withdrawal generally present 6-24 hours following the individual's last drink. The clinical course varies significantly and may be influenced by a number of factors, including comorbid psychiatric and medical conditions. Serious complications (Table 23-9) occur in a minority of patients. Because chronic alcohol consumption is often associated with nutritional deficiencies, vitamin supplementation is essential. Thiamine (before glucose) is also administered to prevent the potential development of Wernicke's encephalopathy and Korsakoff's psychosis.

Several medication treatment protocols have been recommended to manage acute alcohol withdrawal. Short- and long-acting benzodiazepines, however, have been considered medications of choice. Trained medical personnel can use the CIWA-Ar (Figure 23-2) to monitor the patient by rating alcohol withdrawal severity so that medications can be administered appropriately. The CIWA-Ar can also signal possible increased risk for the development of more serious complications, such as delirium tremens and seizures. Patients with a history of seizures secondary to alcohol withdrawal generally are administered long-acting benzodiazepines regardless of CIWA-Ar rating.

Relapse Prevention

The primary focus following successful detoxification from alcohol is maintaining abstinence through relapse prevention. With varying degrees of success, abstinence is maintained through programs that provide psychosocial support via group therapy. Advances in evidence-based behavioral therapy interventions (Table 23-10) aimed at increasing motivation to abstain, enhancing coping skills, facilitating self-change, and dealing with adverse life events have shown benefit. Adverse life events in particular are associated with worse outcomes, whereas social support strategies are linked to long-term remission and abstinence (Satre et al. 2012). Research aimed at deciphering the neuro-biological mechanisms responsible for alcohol dependence has led to effective medications, and results from the COMBINE study indicate that combining behavioral interventions with pharmacotherapies increases the probability of a positive clinical outcome (Gueorguieva et al. 2010).

Alcohol influences multiple neurotransmitter systems in the brain, indirectly increasing DA levels within mesocorticolimbic circuits that mediate its reinforcing effects. Logically, medications that are used to treat alcohol use disorder target these systems. The U.S. Food and Drug Administration (FDA) has approved four medications for the treatment of alcohol use disorder (Table 23-11).

Two formulations of naltrexone are available: oral and extended-release injectable. Results from a majority of clinical trials demonstrate that the competitive μ opioid receptor antagonist naltrexone reduces relapse rates and heavy drinking days (Rösner et al. 2010). Alcohol increases endogenous opioids that act on DA-containing neurons located in limbic circuits responsible for alcohol's reinforcing effects. Naltrexone blocks μ opioid receptors, preventing alcohol-induced increases in central DA linked to the pleasant or positive subjective effects of the drug. This mechanism may be responsible for the ability of naltrexone to reduce craving and heavy drinking (Rösner et al. 2010).

Although the precise mechanisms remain to be elucidated, the glutamate modulator acamprosate is hypothesized to normalize glutamatergic/GABA dysregulation associated with chronic alcohol consumption and withdrawal. In general, acamprosate has shown modest efficacy as a pharmacotherapy for alcohol use disorder. Evidence does suggest that it may decrease the rate of relapse and increase the time of abstinence but not reduce the number of heavy drinking days (Witkiewitz et al. 2012).

Note. NMDA=N-methyl-D-aspartate; tid=three times a day.

Disulfiram, which has been available for over 50 years, facilitates abstinence and decreases the incidence of relapse and heavy drinking days. Disulfiram is believed to decrease alcohol use by blocking the enzyme aldehyde dehydrogenase, thereby increasing acetaldehyde, which is responsible for the so-called disulfiram reaction, which is aversive (Figure 23-4). However, disulfiram also blocks DA 13-hydroxylase, the enzyme responsible for the conversion of DA to norepinephrine (NE) centrally. Decreases in NE neurotransmission have also been linked to disulfiram's therapeutic effects.

In general, accumulating evidence on efficacy and safety more consistently favors naltrexone monotherapy or naltrexone in combination with behavioral therapy interventions for the treatment of alcohol use disorder (Rösner et al. 2010). Importantly, a well-designed clinical trial showed that naltrexone compared with acamprosate treatment was associated with sustained efficacy up to 1 year after the medication was discontinued (Donovan et al. 2008). Medical management combined with naltrexone appears superior to acamprosate based on cost and effectiveness. The injectable formulation of naltrexone has added benefit for noncom-pliant patients or those who may have difficulty taking the medication on a regular basis (Rösner et al. 2010).

Medical Complications

Studies suggest that moderate alcohol consumption (2 drinks/day for men, 1 drink/day for women) is protective against certain diseases, whereas chronic heavy alcohol consumption is associated with serious and often fatal medical complications (see Table 23-9, "Consequences of chronic heavy alcohol consumption"). More specifically, heavy alcohol consumption was the primary risk factor among 51,400 individuals who died due to liver cancer in the United States from 1999 to 2006 (Dong et al. 2011). There is a linear correlation between alcohol intake and the occurrence of cancers of the oral cavity, pharynx, larynx, and esophagus that is influenced by genetic background. Cardiomyopathy, gastritis, hypertension, hemorrhagic stroke, pancreatitis, and polyneuropathy are linked to heavy alcohol use. Alcohol consumption is also a major contributing factor in accidents that result in serious injury and death. Thiamine (vitamin B_:) deficiency due to poor nutrition and hyperemesis in alcohol-dependent individuals can result in Wernicke's encephalopathy, which can be successfully reversed with vitamin supplementation. Onset may be subacute or acute, characterized by confusion, truncal ataxia, and possible withdrawal symptoms. Glucose/dextrose or carbohydrate administration can facilitate the onset of Wernicke's encephalopathy; therefore, thiamine should always be administered first. Magnesium levels should also be determined because sufficient levels of both thiamine and magnesium are required for a positive clinical outcome. If low thiamine and magnesium levels are not restored to normal, approximately 80% of patients may develop Korsakoff's syndrome, a debilitating neurological disorder characterized by profound anterograde amnesia with prominent confabulation.

High amounts of alcohol consumed by pregnant women during gestation can cause numerous complications and adverse outcomes. These include premature birth, low birth weight, spontaneous abortions, and fetal alcohol spectrum disorders (which include fetal alcohol syndrome). Box 23-4 presents the DSM-5 proposed criteria for neurobehavioral disorder associated with prenatal alcohol exposure, which is included as a condition for further study in DSM-5 Section III. The abnormalities that make up fetal alcohol spectrum disorders include cognitive impairment (IQ below 70), growth impairment, syndactyly, septal heart defects, shortened palpebral fissures, flattened nose, thin upper lip (vermilion), and absent philtrum (flattened groove between the upper lip and nose).

Figure 23-4. Alcohol use disorder: disulfiram mechanism of action.

Gender, Age, and Cultural/Ethnic Considerations

Alcohol use disorders are influenced by numerous factors. Males have higher rates of drinking and alcohol-related disorders than females; however, due to physiological factors, women develop higher BAC levels per drink compared with men, which may predispose women to develop alcohol-induced diseases. Indeed, the association of heavy alcohol use with death from hepatocellular carcinoma is stronger for women than for men. Similarly, underage women are at greater risk of being in an alcohol-related automobile crash compared with men. Women, however, are more likely than men to seek professional help for alcohol use disorder.

The earlier that adolescents regularly drink alcohol to intoxication, the greater the risk is that they will develop alcohol use disorder later in life. Data from the National Longitudinal Study of Adolescent Health indicate that alcohol is one of the major causes of premature death among adolescents (Feigelman and Gorman 2010). Older individuals are more susceptible to the toxic effects of alcohol, which often associate with other medical complications.

A family history of alcohol use disorder is well known to impose significant risk of developing the condition. Evidence also reveals the importance of ethnicity in alcohol use disorders. Alcohol withdrawal severity is greater and mortality secondary to alcohol-induced liver disease is higher among non-Hispanic whites. A large study including individuals ages 60 years and older (N=18,772) found that the prevalence of binge drinking was highest among non-Hispanic whites and lowest among Asians (Bryant and Kim 2012). Differences in response to alcohol observed between ethnic groups can partially be attributed to gene variants (alleles) that provide protection or increase risk. For example, gene variants of the alcohol-metabolizing enzymes alcohol dehydrogenase and aldehyde dehydrogenase are most often seen in Asians and affect how these individuals respond to alcohol (Eng et al. 2007). Individuals who carry the alcohol dehydrogenase allele ADH1C IIe, for example, experience an adverse reaction (i.e., skin flushing) upon alcohol ingestion that limits their consumption, thereby lowering their risk of developing alcohol use disorder and liver cirrhosis. Males and females of different ethnic origins who carry another variant of this gene, ADH1B*2, are also protected.

Individuals with preexisting schizophrenia or bipolar disorder, blunted response (low sensitivity) to alcohol, and impulsivity are at high risk for developing alcohol use disorders (Schuckit et al. 2011; Yip et al. 2012). Genetic polymorphisms related to impulsivity and blunted response to alcohol include variants in GABA (e.g., GABAR A2 and A6), acetylcholine (CHRM2), DA (DRD2-ANKK1), and glutamate (GRM3) receptors; DA (SLC6A3) and serotonin (SLC6A4) transporters; and potassium channel (KCNMA1) (Rietschel and Treutlein 2013).

Caffeine-Related Disorders

Epidemiology

DSM-5 caffeine-related disorders encompass caffeine-induced disorders (intoxication and withdrawal) only. Caffeine is the most commonly used mood-altering drug in the world. Caffeine is present in clinically significant quantities in coffee (more in brewed than instant), tea, caffeinated sodas, "energy" drinks, and over-the-counter diet and alertness aids (e.g., NoDoz, Vivarin). Some brands of soda (e.g., Jolt, Red Bull) and coffee (e.g., Shock Coffee, Java Monster) cater specifically to those seeking higher doses of caffeine. Lesser amounts are found in nonprescription pain treatments (e.g., Anacin, Cafergot), chocolate, and milk chocolate. About 15% of adults report ever using a caffeine-containing weight loss product, and women were about twice as likely as men to report use. Of these, about 10% report using the product for over 1 year, but only about one-third of these discussed use with a physician (Blanck et al. 2007). Some caffeine users display symptoms consistent with problematic use, including tolerance and withdrawal.

Intoxication

The prevalence of caffeine intoxication (Box 23-5) in the general population is unclear. Approximately 7% of individuals in the population may experience five or more symptoms along with the functional impairment consistent with a diagnosis of caffeine intoxication. Mild sensory disturbances (e.g., ringing in the ears, flashes of light) may occur with high doses of caffeine. Although large doses of caffeine can increase heart rate, smaller doses can slow heart rate. Whether excess caffeine intake can cause headaches is unclear. On physical examination, agitation, restlessness, sweating, tachycardia, flushed face, and increased bowel motility may be seen. Consistent with caffeine's half-life of approximately 4-6 hours, caffeine intoxication symptoms usually remit within the first day or so and do not have any known long-lasting consequences. However, individuals who consume very high doses of caffeine (i.e., an overdose of 5-10 g) require immediate medical attention, because such doses can be lethal (Wolk et al. 2012).

Withdrawal

The essential feature of caffeine withdrawal (Box 23-6) is the presence of a characteristic withdrawal syndrome that develops after the abrupt cessation of or reduction in regular caffeine ingestion following prolonged daily use. Symptoms usually begin 12-24 hours after the last caffeine dose and peak after 1-2 days of abstinence. Caffeine withdrawal symptoms last for 2-9 days, with the possibility of withdrawal headaches for up to 21 days. Symptoms usually remit rapidly (30-60 minutes) after reingestion of caffeine.

Headache is the hallmark feature of caffeine withdrawal and may be diffuse, gradual in development, throbbing, severe, and sensitive to movement. The incidence of withdrawal headache is about 50% following abrupt cessation of regular caffeine intake. Typically, headaches begin within 12-24 hours after abstinence, reach peak intensity by 48 hours, and can last for more than a week. As expected, withdrawal symptom severity is increased for individuals who had been taking higher daily doses, although abstinence from doses as low as 100 mg/day can produce symptoms. Other symptoms of caffeine withdrawal can occur in the absence of headache. A significant component of caffeine's reinforcing effects can be accounted for by the avoidance of withdrawal symptoms.

Because caffeine ingestion is often integrated into social customs and daily rituals (e.g., coffee break, tea time), some caffeine consumers may be unaware of their dependence on caffeine. Thus, caffeine withdrawal symptoms could be unexpected and misattributed to other causes (e.g., flu, migraine). Furthermore, caffeine withdrawal symptoms may occur when individuals are required to abstain from foods and beverages prior to medical procedures or when a usual caffeine dose is missed due to a change in routine (e.g., during travel, weekends). Similar considerations would apply to changes in daily behavior for religious reasons, such as during Ramadan or Lent.

The symptoms associated with caffeine withdrawal are relatively nonspecific and can be reproduced by a wide range of other medical disorders, including infections, sleep disturbances, thyroid disorders, and anxiety disorders. Additionally, similar symptoms can result from withdrawal from opiate medications, and occasionally withdrawal from other sedative-hypnotic medications. More than 85% of adults and children in the United States regularly consume caffeine, with adult caffeine consumers ingesting about 280 mg/day on average. The incidence and prevalence of the caffeine withdrawal syndrome in the general population is unclear, but it is likely to be high. Headache may occur in approximately 50% of cases of caffeine abstinence (Juliano and Griffiths 2004).

In attempts to permanently stop caffeine use, more than 70% of individuals may experience at least one caffeine withdrawal symptom (47% may experience headache), and 24% may experience headache plus one or more other symptoms as well as functional impairment due to withdrawal (Hughes et al. 1998). Among individuals who abstain from caffeine for at least 24 hours but are not trying to permanently stop caffeine use, 11% may experience headache plus one or more other symptoms as well as functional impairment (Hughes et al. 1998). Caffeine consumers can reduce the incidence of caffeine withdrawal by using caffeine daily or by limiting the frequency of caffeine use (e.g., no more than 2 consecutive days). Gradual reduction of caffeine over a period of days or weeks may decrease the incidence and severity of caffeine withdrawal.

Diagnosis

Obtaining an accurate history of the caffeine use pattern (quantity and frequency) and acute, recent caffeine use is important to making an accurate diagnosis. Care should be taken to include questions regarding use of beverages that may contain caffeine, because the patient may not be aware of the caffeine content. Similar considerations apply to supplements. People often underestimate their level of caffeine intake. Caffeine levels in urine or blood may also provide important information for diagnosis, particularly when the individual is a poor historian. Impairment from caffeine intoxication may have serious consequences, including dysfunction at work or school, social indiscretions, or failure to fulfill role obligations. Moreover, extremely high doses of caffeine can be fatal. In some cases, caffeine intoxication may precipitate a caffeine-induced disorder. Typical dietary doses of caffeine have not been consistently associated with medical problems. However, relatively modest use (e.g., 400 mg) can cause or exacerbate anxiety and somatic symptoms and gastrointestinal distress. With acute, extremely high doses of caffeine, seizures and respiratory failure may result in death. Excessive caffeine use is common among individuals with depressive, bipolar, eating, psychotic, sleep, or substance-related disorders, whereas individuals with anxiety disorders are more likely to avoid caffeine.

Medical Complications

Caffeine withdrawal symptoms can vary from mild to extreme, and may cause functional impairment in normal daily activities. Rates of functional impairment range from 10% to 55% (median 13%) (Ju-liano and Griffiths 2004). Examples of functional impairment include being unable to work, exercise, or care for children; staying in bed all day; missing religious services; ending a vacation early; and canceling a social gathering. Caffeine withdrawal headaches may be described by individuals as "the worst headaches" ever experienced. Decrements in cognitive and motor performance have also been observed.

Caffeine abstinence after regular use has been shown to be associated with impaired behavioral and cognitive performance and increased cerebral blood flow velocity measured using transcranial Doppler. Decreased motivation to work and decreased sociability have also been reported during caffeine withdrawal (Ju-liano and Griffiths 2004). Increased analgesic use during caffeine withdrawal has been documented, most likely to treat caffeine withdrawal headaches.

Gender, Age, and Cultural/Ethnic Considerations

Caffeine is unique in that it is a behavior-ally active drug that is consumed by individuals of nearly all ages. Although caffeine withdrawal among children and adolescents has been documented, relatively little is known about risk factors for caffeine withdrawal among this age group. The use of highly caffeinated energy drinks may be increasing among young people, which could increase the risk for caffeine withdrawal and other medical complications (Wolk et al. 2012). Caffeine intoxication among young individuals after consumption of highly caffeinated products, including energy drinks, has been observed. Children and adolescents may be at increased risk of caffeine intoxication due to low body weight, lack of tolerance, and lack of knowledge about the pharmacological effects of caffeine. Rates of caffeine consumption and the overall level of caffeine consumption increase with age until the early to mid-30s and then level off. With advancing age, individuals are likely to demonstrate increasingly intense reactions to caffeine, with greater complaints of interference with sleep or feelings of hyperarousal. Habitual consumers of caffeine who fast for religious reasons may be at increased risk for caffeine withdrawal.

Cannabis-Related Disorders

Epidemiology

According to the 2011 National Survey on Drug Use and Health, 29.3% of persons ages 12 years and older used cannabis at least once in the prior year, and 4.5 million persons were classified as dependent on or abusing marijuana (Substance Abuse and Mental Health Services Administration 2012b). In 2010, there were 2.4 million recent cannabis initiates, 58.5% of whom were younger than age 18 years (Substance Abuse and Mental Health Services Administration 2012b). Marijuana produces dependence (i.e., cannabis use disorder) in 9% of those who try it (National Institute on Drug Abuse 2012). Distressingly, data showed that 1.4 million youths ages 12-17 were current cannabis users in 2011, and the number of daily users among this age group rose sharply from 2009 to 2011, which is in contrast to the considerable decline of use during the preceding decade (Substance Abuse and Mental Health Services Administration 2012b). In addition, the recent availability of so-called synthetic cannabinoid-like compounds (e.g., "K2" and "spice"), which are associated with psychosis and adverse cardiovascular events in young individuals, has highlighted the urgency of addressing cannabis use disorders (Mir et al. 2011). The DSM-5 criteria for cannabis use disorder are presented in Box 23-7.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Intoxication and Withdrawal

Acute intoxication with cannabis can manifest as impaired motor coordination, euphoria, and time perception difficulty (Box 23-8). Numerous studies suggest that the time-dependent set of withdrawal symptoms (Box 23-9, Criterion B) experienced when cannabis users are trying to quit makes it difficult for them to stop using the drug on their own. One study found that cannabis craving contributed less to relapse than did the affective withdrawal syndrome (Budney et al. 2008), which is characterized by irritability, anxiety, depressed mood, decreased appetite, and sleep difficulty, and which displays similar scope and severity to the withdrawal associated with tobacco use (see section "Tobacco-Related Disorders" later in this chapter).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Diagnosis and Treatment

The DSM-5 diagnosis of cannabis use disorder (see Box 23-7) is similar in structure to the diagnoses set forth for other addictive drugs. Findings from the Treatment Episode Data Set (TEDS) revealed that 54.3% of daily cannabis users admitted for treatment reported having at least one prior treatment episode; 8.9% reported five or more prior episodes (Substance Abuse and Mental Health Services Administration 2012c). These data highlight the high rates of relapse associated with current treatment options for cannabis dependence, which are comparable to rates found for other drugs of abuse. Although systematic research on treatments for cannabis use disorders began approximately 20 years ago, treatment admissions for cannabis use disorders in the United States have increased twofold during the past decade, and both the absolute number (1 million) and the percentage of total treatment admissions for all illicit drugs (32%) were greater for marijuana than for any other illicit drug in 2010.

Psychosocial and Pharmacological Treatments

To date, the most effective means to treat cannabis use disorder is the use of behavioral therapies, including cognitive-behavioral therapy. A major obstacle slowing the development of treatments for cannabis abuse is the continued belief that cannabis is benign and incapable of inducing true addiction. Like all addictive drugs, cannabis increases DA release in the mesolimbic reward pathway, which is thought to drive compulsive drug use despite the presence of adverse effects. Moreover, scientific studies clearly indicate that regular cannabis use is strongly associated with a greater risk of illicit drug dependence or abuse, poor academic performance, poor job performance, increased absences from work, cognitive deficits, mental illness, and lung damage, among other ramifications.

A study of cannabis users found that those carrying a genetic variant that favors hyperactivity of the endocannabinoid (eCB) system were significantly less likely to become cannabis dependent (Clapper et al. 2009). Consistent with this idea, clinical studies have shown that cannabinoid replacement therapy with oral A⁹-tetrahydrocannabinol (THC), the primary psychoactive constituent in cannabis, attenuates withdrawal symptoms in daily cannabis users (Haney et al. 2004). However, similar doses of cannabis exhibited reinforcing properties in healthy male cannabis users, suggesting that abuse liability remains a concern. An alternative approach to cannabinoid replacement therapy is to enhance eCB signaling. Available studies indicate that eCB signaling mediates anxiolytic-like and antidepressant-like effects, as well as responses to rewarding stimuli, and thus provide strong support for the notion that elevating eCB levels in people seeking treatment for cannabis use disorder will restore normal eCB functioning, reduce withdrawal symptoms, and ultimately decrease recidivism.

Medical Complications

Heavy cannabis use by adults can cause deficits in attention and memory functions that are subtle and not clinically disabling, although heavy cannabis use during adolescence might have a more devastating impact on cognitive functions that are actively maturing. Indeed, marijuana use before age 17 has been associated with more severe cognitive deficits and smaller cortical gray matter volumes. Moreover, relative to cannabis use during adulthood, use during adolescence is associated with altered neural activation patterns, greater neuropsychological deficits, and an increased risk of developing schizophrenia (Rapp et al. 2012).

Nearly three-quarters of current cannabis users (74%) also smoke tobacco, and an estimated 7 million Americans currently smoke both substances. Among individuals with cannabis use disorder, tobacco smokers have poorer cannabis cessation outcomes, which may be due to the fact that both cigarettes and cannabis are smoked and thus the smoking cues associated with continuing tobacco use might intensify the withdrawal associated with quitting cannabis use (Haney et al. 2013).

Hallucinogen-Related Disorders

Epidemiology

According to the 2011 National Survey on Drug Use and Health, more than 1.1 million persons ages 12 and older used hallucinogens within the past year (Substance Abuse and Mental Health Services Administration 2012b). It is unclear whether early age at onset is associated with elevations in risk for developing hallucinogen use disorder. Use patterns have been found to differ by age at onset, with early-onset users of 3,4-methylenedioxymethamphetamine (MDMA, commonly called "Ecstasy") more likely to be polydrug users (Wu et al. 2009a). Compared with the use of other hallucinogens, the use of MDMA increases the risk of developing a hallucinogen use disorder (Wu et al. 2009b). Little is known regarding the course of either phencyclidine use disorder (Box 23-10) or other hallucinogen use disorder (Box 23-11), but both are generally thought to have low incidence, low persistence, and high recovery rates.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Hallucinogens comprise a diverse group of substances that, despite having different chemical structures and possibly molecular mechanisms, produce similar alterations of perception, mood, and cognition in users. Included are three main chemical classes: phencyclidine and related drugs (e.g. ketamine), the phenylalkylamines (e.g., mescaline, 2,5-dimethoxy-4-methylamphetamine [DOM], and MDMA) and the indoleamines, including tryptoamines (psilocybin and dimethyl-tryptamine [DMT]) and ergolines (LSD and morning glory seeds) (Halberstadt and Geyer 2011). In addition, miscellaneous other ethnobotanical compounds are classified as hallucinogens, of which Salvia divinorum (salvia) and Datura stramonium (jimsonweed) are two examples. Cannabis and its active compound THC are excluded from the hallucinogen group (see the section "Cannabis-Related Disorders" earlier in this chapter). These substances can have hallucinogenic effects but are treated separately in DSM-5 because of significant differences in their psychological and behavioral effects.

Hallucinogens are usually taken orally, although some forms are smoked (e.g., DMT, salvia) or, more rarely, taken intranasally or by injection (e.g., MDMA). Duration of effects varies across types of hallucinogens. Some (LSD, MDMA) have a long half-life and extended duration of action, such that users may spend hours to days using and/or recovering from their effects. Other hallucinogenic drugs (e.g., DMT, salvia) are short acting. Tolerance quickly develops to both autonomic and psychological effects of hallucinogens. There is cross-tolerance between LSD and other hallucinogens (e.g., psilocybin, mescaline), but cross-tolerance does not extend to other drug categories such as AMPH and cannabis.

MDMA may have distinctive hallucinogenic and stimulant properties because it shares pharmacological features with AMPH. Among heavy MDMA users, tolerance, use despite physical or psychological problems, hazardous use, and spending time engaged in drug-related activities are the most commonly reported symptoms or behaviors, each reported by more than 50% of adults meeting criteria for other hallucinogen use disorder (Cottier et al. 2009). Both psychological and physical problems are commonly endorsed, with feeling depressed, feeling tired, change in appetite, trouble concentrating, feeling anxious, sleep difficulties, and headache among the most frequent (endorsed by 30% or more of those meeting use disorder criteria). Nevertheless, a clinically significant withdrawal syndrome has not been consistently documented objectively in humans; therefore, the diagnosis of hallucinogen withdrawal syndrome is not included in DSM-5. As found for other substances, symptoms associated with hallucinogen use disorder are arrayed along a single severity continuum.

Intoxication

Phencyclidine intoxication (Box 23-12) and other hallucinogen intoxication (Box 23-13) reflect the clinically significant behavioral or psychological changes that occur shortly after ingestion of the respective substance. Depending on the specific hallucinogen, the intoxication may last only minutes (e.g., for salvia) or may last several hours or longer (e.g., for LSD or MDMA). Symptoms typical of hallucinogens can be produced by other drugs. Phencyclidine and ketamine can produce hallucinations, although their use is also associated with prominent dissociative symptoms. Highly potent cannabis can produce hallucinations, especially among naive users. Khat, a plant that contains cathinone, produces symptoms similar to those of MDMA.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Diagnosis

Other mental illnesses can cause symptoms resembling those produced by hallucinogens. Schizophrenia and bipolar mania produce hallucinations and other psychotic symptoms, but these states differ from drug effects because of their chronicity. Rarely, symptoms of hallucinogenic drugs overlap with those of panic disorder, alcohol or sedative withdrawal, or general medical conditions (e.g., seizure disorder, stroke, ophthalmological disorder, central nervous system [CNS] tumor).

Hallucinogen intoxication should be differentiated from intoxication from AMPH, cocaine or other stimulants, anticholinergics, inhalants, or phencyclidine. Toxicological tests are useful in making this distinction, and determining the route of administration may also be useful. Phencyclidine and ketamine usually cause dissociative symptoms and/or more disruptive behavior, whereas cannabis usually causes more modest symptoms. Other conditions to be considered include acute schizophrenia, depression, withdrawal from other drugs (e.g., sedatives, alcohol), CNS tumors, seizure disorders, vascular insults, and certain metabolic disorders such as hypoglycemia. Metabolic derangements and other medical conditions can cause delirium, which can resemble hallucinogen intoxication. Delirium caused by other medical conditions can generally be distinguished from hallucinogen intoxication because the former is associated with alteration in level of consciousness.

Hallucinogen intoxication is distinguished from hallucinogen persisting perception disorder (Box 23-14) by the fact that the latter continues episodically or continuously for weeks (or longer) after the most recent intoxication. Hallucinogen persisting perception disorder is usually associated with less compelling visual hallucinations, perhaps verging into illusions. Most people experiencing hallucinogen persisting perception disorder recognize the symptoms and are not particularly disturbed by them.

Medical Complications

There is evidence for persistent neurotoxic effects of MDMA use, including impairments in memory, psychological function, neuroendocrine function, serotonin system, and sleep disturbance. Effects on brain microvasculature, white matter maturation, and damage to axons, may result in decreases in verbal memory. Use of MDMA may diminish connections among brain regions. Regular use of peyote as part of religious rituals is not linked to neuropsychological or psychological deficits, however (Halpern et al. 2005).

Distinguishing the effects of hallucinogens from those of other substances (e.g., phencyclidine and AMPH) is required, especially because contamination of the hallucinogens with other drugs is relatively common. Schizophrenia also must be ruled out, because some individuals with schizophrenia (e.g., those who exhibit paranoia) may falsely attribute their symptoms to the use of hallucinogens. Other potential disorders and conditions to be ruled out include panic disorder, depressive and bipolar disorders, alcohol or sedative withdrawal, hypoglycemia and other metabolic conditions, seizure disorder, stroke, ophthalmological disorder, and CNS tumors. Careful history of drug taking, collateral reports from family and friends (if possible), age, clinical history, physical examination, and toxicology reports should be useful in arriving at the final diagnostic decision.

Adolescents who use MDMA and other hallucinogens have a higher prevalence of other substance use disorders. Individuals who use hallucinogens (particularly MDMA and salvia) have a higher rate of non-substance-related psychiatric disorders (especially anxiety, depressive, and bipolar disorders). Rates of antisocial personality disorder (but not conduct disorder) are elevated among individuals with hallucinogen use disorder, as are rates of adult antisocial behavior. However, it is unclear whether the concomitant psychiatric illnesses may be precursors to rather than consequences of hallucinogen use disorder (see earlier section "Epidemiology").

Impairments due to hallucinogen intoxication can have serious consequences. The perceptual disturbances and impaired judgment associated with hallucinogen intoxication can result in injuries or fatalities from automobile crashes, physical fights, or unintentional self-injury (e.g., attempts to "fly" from high places). Environmental factors and the personality and expectations of the individual using the hallucinogen may contribute to the nature of and severity of hallucinogen intoxication.

Gender, Age, and Cultural/Ethnic Considerations

In adults the prevalence of hallucinogen-related disorders is higher in males (0.2%) than in females (0.1%), but in adolescents the 12-month prevalence in females (0.6%) slightly exceeds that of males (0.4%). Rates decrease to virtually 0% among individuals ages 45 and older. Adult men and women with hallucinogen-related disorders report similar symptoms (Ker-ridge et al. 2011). However, in adolescents, females may be less likely than males to endorse "hazardous use," and female gender may be associated with increased odds of hallucinogen use disorder. This disorder is observed primarily in individuals under age 30 years, and occurrence is extremely rare among older adults.

Hallucinogen use and associated problems have increased recently among adolescents in the United States and several other countries (United Nations Office on Drugs and Crime 2012). According to Wu et al. (2006), 7.8% of youths ages 16-23 reported using one or more hallucinogens in the previous 12 months, with MDMA being the preferred type. Few surveys, however, directly estimate the extent of hallucinogen use disorders. Currently, no data are available on hallucinogen use disorders across countries to suggest any trends.

There are marked ethnic differences in 12-month prevalence of other hallucinogen use disorder (American Psychiatric Association 2013). Among adolescents, 12-month prevalence is higher among

American Indians and Alaska Natives (1.2%) than among Hispanics (0.6%), whites (0.6%), African Americans (0.2%), and Asian Americans and Pacific Islanders (0.2%). Among adults, 12-month prevalence of hallucinogen use disorder is similar for American Indians and Alaska Natives, whites, and Hispanics (all 0.2%), but somewhat lower for Asian Americans and Pacific Islanders (0.07%) and African Americans (0.03%).

Historically, hallucinogens have been used as part of established religious practices, such as the use of peyote in the Native American Church. Ritual use of psilocybin obtained from certain types of mushrooms occurs in South America, Mexico, and some areas in the United States. Ayahuasca prepared from hallucinogenic plants is used by the Santo Daime and Uniao de Vegetal sects in Brazil. For adults, no racial or ethnic differences for either full or individual DSM-5 criteria are apparent at this time.

Inhalant-Related Disorders

Epidemiology

Inhalant use disorder (Box 23-15) is rare, yet it affects a very young and vulnerable population. Of approximately 3 million individuals ages 12 years and older who used an illicit drug for the first time in 2011, 9% reported inhalants as their first drug (Substance Abuse and Mental Health Services Administration 2012b). Of individuals who were admitted for treatment of inhalant use disorder, 29% were between the ages of 12 and 17 years (Howard et al. 2011). Inhalant use involves the purposeful inhalation of toxic vapors from a variety of inexpensive and readily available commercial products to achieve intoxication. Solvents (paint thinner), gases (gasoline), cleaning agents (degreasers), aerosols (spray paint, hair spray), anesthetics (nitrous oxide), glues (airplane glue), and adhesives are commonly used. Some individuals inhale vapors directly from a container, a bag, or a chemical-soaked rag placed close to the nose and mouth (the latter is termed huffing). Other examples include glading, the inhalation of air-freshener aerosols, and dusting, the inhalation of computer electronics cleaning products by placing the container straw directly into the mouth or nose.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Inhalants may contain many toxic chemicals. Products that contain toluene, acetone, chlorofluorocarbons, benzene, xylene, hexane, and butane are preferred by those with inhalant use disorder (Howard et al. 2011). The neurobiological mechanisms that mediate the reinforcing effects of inhalants are unknown. Studies in animals indicate that inhalants increase central DA, possibly through GABA and N-methyl-D-aspartate (NMDA) receptors or by directly stimulating DA release in mesolimbic circuits (Riegel et al. 2007).

Intoxication and Withdrawal

Acute inhalant intoxication (Box 23-16) produces effects similar to alcohol intoxication. Symptoms include dizziness, incoordination, slurred speech, unsteady gait, depressed reflexes, generalized muscle weakness, blurred vision, diplopia, and euphoria, among others. Although there is no clearly defined withdrawal syndrome for inhalant use, some symptoms appear to be similar to those of cocaine withdrawal.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Diagnosis

No laboratory or diagnostic tests are currently available to identify inhalant use disorder. Recent research has focused on tests to detect metabolites of toluene, but these are not readily available for clinical use. Diagnosis can be supported by documented inhalant intoxication, standard drug screens to exclude other substances, odors, possession of inhalants or drug paraphernalia, and the presence of perioral or perinasal ("glue-sniffer's rash") lesions. Populations that are at higher risk of inhalant use disorder include young people (especially homeless children) who are members of ethnic groups with a high rate of inhalant use (e.g., some native or aboriginal communities) and employees in occupations that allow easy access to inhalants.

Medical Complications and Treatment

Chronic inhalant use is associated with altered brain perfusion and blood flow as well as structural abnormalities in specific areas linked to cognitive deficits. Neurological symptoms associated with Parkinson's disease, motor impairment, decreased muscle strength, peripheral and sensorimotor neuropathy, speech problems, and tremor are associated with inhalant use. Studies consistently associate inhalant use with impaired executive functioning and working memory, poor concentration, reduced IQ, depression, inattention, insomnia, and memory loss (Howard et al. 2011). Suicidal ideation and psychosis are notable psychiatric consequences related to inhalants. Data from inhalant cases reported to U.S. poison control centers indicate that butane, propane, and air fresheners resulted in the highest fatality rates (Marsolek et al. 2010). Fatalities linked to inhalant use are commonly a result of cardiovascular complications such as myocardial ischemia from hypoxia, arrhythmias, and ventricular fibrillation. Death can also result from anoxia, aspiration, asphyxia, respiratory depression, and trauma. Inhalant use also has serious adverse effects on pulmonary function, resulting in coughing and wheezing, dyspnea, emphysema, pneumonia, and other pulmonary diseases. Liver toxicity, acute renal failure, and bone marrow suppression leading to anemia and leukemia relate to chronic inhalant use. Treatment in the context of acute toxicity or organ failure is supportive, addressing the relevant medical complications.

Psychosocial and Pharmacological Treatments

Very few studies have evaluated potential psychosocial and pharmacological treatments for inhalant use disorder. Case reports and small clinical trials, however, do suggest success with risperidone, haloperidol, carbamazepine, and lamotrigine in treating paranoid psychosis associated with chronic inhalant use and inhalant craving following a period of abstinence.

Gender, Age, and Cultural/Ethnic Considerations

The prevalence of inhalant use disorder is almost identical in adolescent males and females; however, the disorder is very rare among adult women. Prevalence also decreases dramatically among individuals in their 20s. Adolescent females appear to prefer air fresheners, hair sprays, and nail polish or remover, whereas adolescent males are more likely to inhale gasoline (Marsolek et al. 2010). High rates of inhalant use exist among native or aboriginal communities and in areas with large populations of homeless children.

Opioid-Related Disorders

Epidemiology

Opiate analgesics are some of the oldest and most common medications for helping patients but also have been abused since 300 B.C. Since 2007, prescription opiates have surpassed marijuana as the most common illicit drug that adolescents initially abuse, and in the United States, the 0.14% annual prevalence of heroin dependence is only about one-third the rate of prescription opiate abuse (Substance Abuse and Mental Health Services Administration 2010). This rate also is substantially lower than the 2% rate of morphine dependence in Southeast and Southwest Asia (United Nations Office on Drugs and Crime 2012). These rates are low relative to other abused substances, but their disease burden is substantial, with high rates of morbidity and mortality, disease transmission, increased health care, crime and law enforcement costs, and less tangible costs of family distress and lost productivity.

Opioid use disorder (Box 23-17) is defined as chronic and compulsive use of opioids that cannot be justified medically and that produces specific signs and symptoms. Often, however, a medical condition does exist that requires opioid analgesics, but the doses administered exceed those generally required for appropriate therapy. Opioids may be obtained by illegal purchase, but more than ever they are obtained from physicians. Tolerance develops to chronic opioid administration, which requires increased dosing over time. Abrupt cessation of opioid administration results in a significant withdrawal syndrome that promotes relapse and continued drug intake. Individuals with opioid use disorder respond differently to environmental cues associated with drug self-administration. Drug-associated cues may contribute to the inability to maintain abstinence following detoxification.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

The most commonly abused opiate is oxycodone, followed by heroin and morphine, and then—among health professionals—meperidine and fentanyl. These drugs are often obtained through diverted prescriptions. Two opiate maintenance treatment agents, methadone and buprenorphine, are abused at substantially lower rates, and the partial opiate agonists, such as butorphanol, tramadol, and pentazocine, are infrequently abused. One serious complication is when pregnant women dependent on opiates give birth to babies who are born addicted, because neonatal withdrawal leads to seizures and, unless treated, can be fatal. The rate of neonatal dependence has risen more than sixfold in the past 10 years due to prescription opiate abuse.

Intoxication

The "high" from opioids occurs only when the rate of change in brain DA is fast. Large, rapidly administered doses of opiates block GABA inhibition and produce the burst of NAc activity that is associated with the "high" of all abused drugs. Therefore, routes of administration that slowly increase opiate blood and brain levels, such as oral and transdermal routes, are effective for analgesia and sedation, but do not produce an opiate "high" as occurs via smoking and intravenous routes. Other acute effects, such as analgesia and respiratory depression leading to overdose, are due to opiate receptors located in other areas such as the locus coeruleus.

The clinical aspects of abuse therefore are tied to route of administration and the rapidity with which an opiate bolus reaches the brain. Intravenous administration is routine not only because it is the most efficient route but also because it rapidly produces a bolus of high drug concentration in the brain. This bolus produces a "rush," followed by euphoria, a feeling of tranquility, and sleepiness ("the nod"). Heroin produces effects that last 3-5 hours, and several doses a day are required to forestall manifestations of withdrawal in dependent persons. The DSM-5 criteria for opioid intoxication are shown in Box 23-18. Management of acute opiate overdose is addressed in Table 23-12.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Withdrawal

Tolerance and withdrawal symptoms commonly occur with chronic daily opiate use beginning as quickly as 6-8 weeks after an individual starts to take an opiate, depending on the dose and frequency of dosing. Tolerance appears to be primarily a pharmacodynamic rather than pharmacokinetic effect, with relatively limited induction of the cytochrome P450 systems of 2D6 and 3A4. The plasma half-lives generally range from 2.5 to 3 hours for morphine; the shortest half-lives of several minutes are for fentanyl-related opiates and the longest are for buprenorphine, which can block opiate withdrawal and other opiates for up to 3 days after a single dose. Tolerance to the mental effects of opioids leads to the need for ever-increasing amounts of drugs to sustain the desired euphoriant effects, as well as to avoid the discomfort of withdrawal. This combination has the expected consequence of strongly reinforcing dependence once it has started.

Symptoms of opioid withdrawal (Box 23-19) begin 8-10 hours after the last dose. Many of these symptoms resemble those of increased activity of the autonomic nervous system (Table 23-13). The acute phase of withdrawal may last 7-10 days. A secondary phase of protracted abstinence lasts 26-30 weeks and is characterized by hypotension, bradycardia, hypothermia, mydriasis, and decreased responsiveness of the respiratory center to carbon dioxide.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Source. Adapted from Collins and Kleber 2004.

Treatment

Clinicians have two general treatment paths: opioid maintenance treatment or detoxification. Agonist and partial agonist medications are commonly used for both maintenance and detoxification purposes; α₂-adrenergic agonists are primarily used for detoxification. Antagonists are used to accelerate detoxification and then continued after detoxification to prevent relapse. Only residential medication-free programs generally have had success that comes close to matching that of the medication-based programs. Success of the various treatment approaches is assessed as retention in treatment and reduction of opioid and other drug use, as well as secondary outcomes of HIV risk behaviors, crime, psychiatric symptoms, and medical comorbidity.

The principles of detoxification are the same for all drugs: to substitute a longer-acting, orally active, pharmacologically equivalent drug for the abused drug, stabilize the patient on the substituted drug, and then gradually withdraw it. Methadone is admirably suited for such use in opioid-dependent persons. Clonidine, a centrally acting sympatholytic agent, has also been used for detoxification. Clonidine has no narcotic action and is not addictive. Lofexidine, a clonidine analog with less hypotensive effect, is being developed for use. Table 23-14 details the use of methadone, clonidine, and buprenorphine for detoxification.

Buprenorphine for Detoxification

Because it is a partial agonist, buprenorphine produces fewer withdrawal symptoms and may allow briefer detoxifications compared with full agonists like methadone, but it does not appear to have better outcomes than methadone tapering. Buprenorphine is superior to the α₂-adrenergic agonist clonidine in reducing symptoms of withdrawal, in retaining patients in a withdrawal protocol, and in treatment completion.

Note. For clonidine-naltrexone protocols, consult one of the "Suggested Readings" texts listed at the end of this chapter.

Methadone Maintenance

Methadone's slow onset of action when taken orally, its long elimination half-life (24-36 hours), and its production of crosstolerance at dosages from 80 to 150 mg are the bases for its efficacy in treatment retention and reductions in intravenous drug use. Methadone can prolong the QT interval at rates as high as 16% above the rates in non-methadone-maintained, drug-injecting patients, but it has been used safely in the treatment of opioid dependence for 40 years.

Buprenorphine Maintenance

In October 2002, the FDA approved sublingual buprenorphine as a Schedule III drug for managing opiate dependence. Unlike the full agonist methadone, buprenorphine is a partial agonist of μ opioid receptors with a slow onset and long duration of action, allowing for alternate-day dosing. Its partial agonism reduces the risk of unintentional overdose but limits its efficacy to patients who need the equivalent of only 60-70 mg of methadone; many patients in methadone maintenance, however, require higher dosages, up to 150 mg daily. Buprenorphine is combined with naloxone at a 4:1 ratio in order to reduce its abuse liability, and it now comes in a film strip that prevents abuse through intranasal crushing and snorting. A subcutaneous buprenorphine implant has also had favorable results but is not yet FDA approved.

Antagonist Medications

Naltrexone, a long-acting orally active pure opioid antagonist, can be given three times a week at doses of 100-150 mg, and a depot form for monthly administration is available. Because it is an antagonist, the patient must first be detoxified from opioid dependence before starting to take naltrexone. When taken chronically for even years, naltrexone is safe, is associated with few side effects (headache, nausea, abdominal pain), and can be given to patients infected with hepatitis B or C without producing hepatotoxicity. However, most providers refrain from prescribing it if liver function tests are 3-5 times above normal levels. Depot injection formulations lasting up to 4 weeks markedly improve adherence, retention, and drug use. Subcutaneous naltrexone implants in Russia, China, and Australia have doubled treatment retention and reduced relapse to half that of oral naltrexone.

Medical Complications

Besides the brain effects of opioids on sedation and euphoria and the combined brain and peripheral nervous system effects on analgesia, a wide range of other organs can be affected. The cough reflex is inhibited through the brain, leading to the use of some opiates as an antitussive, and nausea and vomiting are due to brain stem effects on the medulla. The release of several hormones is inhibited; these include corticotropin-releasing factor and luteinizing hormone, which reduce cortisol and sex hormone levels, respectively. The clinical manifestations of these reductions can involve poor responses to stress and reductions in sex drive. An increase in prolactin also contributes to the reduced sex drive in males. Two other effects are decreased thyrotropin and increased growth hormone. Respiratory depression contributes to overdose, but in patients with pulmonary disease, even opiate doses well below those typical of overdose can produce clinically significant complications. In overdoses, aspiration pneumonia is a common complication due to loss of the choking reflex. Opiates reduce gut motility, which can lead to nausea, constipation, and anorexia with weight loss. The cardiovascular effects of opiates include prolonged QT intervals and sudden death in some patients. Orthostatic hypotension may occur due to histamine release and peripheral blood vessel dilation.

Risks include fatal overdose; hepatitis B, AIDS, and other potential complications of sharing contaminated hypodermic syringes; and bacterial infections that can lead to septic complications such as meningitis, osteomyelitis, and abscesses in various organs. Attempts to illicitly manufacture meperidine have resulted in a highly specific neurotoxin, l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonism in users.

Acute opioid overdose is a relatively common complication that is treated with naloxone to provide a highly specific reversal that is relatively free of complications (see Table 23-12, "Management of acute opioid overdose"). The presentation involves shallow and slow respirations, pupillary miosis (mydriasis does not occur until significant brain anoxia), bradycardia, hypothermia, and stupor or coma. If the individual is not given naloxone rapidly, respiratory and cardiovascular collapse leads to death. At autopsy these individuals have cerebral edema and sometimes frothy pulmonary edema, but those pulmonary effects are most likely from allergic reactions to adulterants mixed with the drug. Opiates generally do not produce seizures except in unusual cases of mixed drug abuse, with the opiate meperidine often involved in these cases.

Gender, Age, and Cultural/Ethnic Considerations

Age, gender, and cultural factors are involved in opioid use disorders. These disorders start typically in adolescence, but prescription abuse due to chronic pain can have a later onset. Increasing age is associated with a decrease in prevalence due to early mortality and the remission of symptoms after age 40 years (i.e., "maturing out"). However, many individuals continue to meet opioid use disorder criteria for decades. The male-to-female ratio typically is 1.5:1 for opioids other than heroin and 3:1 for heroin. Ethnic minority populations living in economically deprived areas are overrepresented, but increasingly white middle-class individuals, especially women, are abusing prescription opioids. Medical personnel who have ready access to opioids also have an increased risk for this disorder.

Sedative-, Hypnotic-, or Anxiolytic-Related Disorders

Epidemiology

DSM-5 criteria for sedative, hypnotic, or anxiolytic use disorder and intoxication are presented in Box 23-20 and Box 23-21, respectively. Estimates of the rates of abuse liability of benzodiazepines and related agents are made based on prescriptions issued, patterns of medical use, misuse by patients with sedative-, hypnotic-, or anxiolytic-related disorders, and national surveys. About 1% of the U.S. population has used a benzodiazepine for 1 year or longer. Approximately 15%-20% of alcoholic patients presenting for treatment may also have an anxiolytic use disorder. In methadone clinics, urine tests positive for benzodiazepines are common, with 30%-90% of patients reporting illicit use. In the 2011 National Survey on Drug Use and Health, 8% of the U.S. population ages 12 years and older reported having used tranquilizers for nonmedical purposes at some time in their life, and 0.7% had used them within the month prior to the survey (Substance Abuse and Mental Health Services Administration 2012b). Alprazolam was the benzodiazepine that was most frequently reported in emergency visits. Benzodiazepines were mentioned in 27% of suicide attempts (Substance Abuse and Mental Health Services Administration 2012b).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Sedative, hypnotic, or anxiolytic substances include prescription medications such as anxiolytics, hypnotics, anticonvulsants, muscle relaxants, and anesthesia induction agents. This class includes benzodiazepines, nonbenzodiazepine hypnotics, barbiturates, and miscellaneous related compounds. Four nonbenzodiazepine hypnotics are included in the class: zopiclone, a cyclopyrolone; eszopiclone, a stereoselective isomer of zopiclone; zaleplon, a pyrazolopyrimidine; and zolpidem, an imidazopyridine. The clinically available formulations of benzodiazepines and related drugs are shown in Table 23-15.

It is generally believed that rapid onset of action of sedative-hypnotic drugs is associated with euphoria. Diazepam and alprazolam have higher abuse potential than halazepam and oxazepam. The most serious drug-drug interactions occur when sedative-hypnotics are combined with alcohol or other drugs that depress CNS activity. Barbiturates present a serious risk of CNS depression, coma, and death when taken in high doses or with ethanol or other sedative-hypnotics. Patients taking phenobarbital also may experience decreased effects of anticoagulants, oral contraceptives, corticosteroids, some antibiotics, and other drugs, due to induction of their metabolism.

Intoxication and Overdose

Tolerance of clinical effects may lead some patients to escalate the dosage. The risk appears to be greatest when the drugs are used as hypnotics, because tolerance of sedation occurs rapidly, but tolerance does not develop to the anxiolytic action of benzodiazepines. The withdrawal syndrome that appears upon decreasing dosage or abrupt discontinuation of treatment may produce uncomfortable mental and physical states that make it difficult for patients to terminate drug use. Rebound insomnia is a particular problem for patients who discontinue benzodiazepines.

^a Butalbital is available in combination with nonopioid analgesics (Fiorinal) and opioid analgesics (Fiorinal with codeine).

Source. www.fda.gov/Drugs.

The benzodiazepines occupy an intermediate position of abuse liability, with barbiturates and older sedative-hypnotics (e.g., methaqualone, ethchlorvynol) having greater risk of abuse, and anxiolytics and hypnotics that act via non-GABAergic mechanisms (e.g., buspirone, antidepressants, ramelteon) lacking abuse potential. The benzodiazepines with the highest liability for abuse are fhmitrazepam, diazepam, alprazolam, and possibly lorazepam. Those with the lowest positive reinforcing effects in humans are clonazepam, chlordiazepoxide, halazepam, prazepam, quazepam, and oxazepam. Postmarketing surveillance indicates a relatively low potential for abuse for zolpidem considering how often it is prescribed.

In patients with anxiety disorders, abuse is not common; however, certain subgroups of patients, such as individuals with alcohol dependence and those in methadone maintenance programs, are at high risk to misuse these agents. Compared with the general population, elderly persons and patients with chronic pain have higher rates of benzodiazepine use; however, there is insufficient evidence to suggest that these groups abuse benzodiazepines. The newer nonbenzodiazepine hypnotics, commonly referred to as the Z drugs, may have a lower potential for abuse, tolerance, and dependence, although they are not devoid of such risk. The identification of GABA_A receptor subtypes and clarification of their function provide hope that drug development will lead to GABA_A agonists and modulators that have fewer adverse effects, lower risk for dependence, and greater specificity of action.

Acute toxicity of benzodiazepines includes sedation, psychomotor impairment, and memory problems. It is well established that acute doses of benzodiazepines produce anterograde amnesia, difficulty acquiring new learning, and sedation that may affect attention and concentration. All sedative-hypnotics produce effects on a continuum from sedation to obtundation. Barbiturates have a greater risk for respiratory depression than do benzodiazepines. In overdose situations, sedative-hypnotics are often combined with ethanol or other CNS depressants. When high doses of benzodiazepines are ingested, either as a therapeutic intervention or overdose, initial signs of toxicity are ataxia and impaired gag reflex. Rarely do sedative-hypnotics produce disinhibition or paradoxical excitement.

Withdrawal

DSM-5 criteria for sedative, hypnotic, or anxiolytic withdrawal are presented in Box 23-22. In its most severe form, a withdrawal syndrome after high-dose chronic administration of chlordiazepoxide or diazepam can include grand mal seizures and psychosis. When one of these drugs is administered for short periods and at therapeutic doses, the withdrawal syndrome is usually mild, consisting of anxiety, headache, insomnia, dysphoria, tremor, and muscle twitching. After long-term treatment with therapeutic doses, the syndrome increases in severity and may include autonomic dysfunction, nausea, vomiting, depersonalization, derealization, delirium, hallucinations, illusions, agitation, and grand mal seizures. The time course of the abstinence syndrome is related to the half-life of the agent. Patients taking agents with short half-lives (lorazepam, alprazolam, temazepam) develop symptoms within 24 hours of discontinuation, with severity peaking at 48 hours. When patients take agents with longer half-lives, such as diazepam, symptoms may develop a week after drug discontinuation and last for several weeks. This timeline should be used as a general guideline, because some patients taking long-acting agents will develop symptoms earlier than predicted by the pharmacokinetics of the drug. In addition, some clinicians believe that there is a prolonged withdrawal syndrome that persists for several months, but it has not been clearly distinguished from return of original anxiety symptoms.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

The withdrawal syndrome from barbiturates occurs after taking 0.8- to 2.2-g/day oral doses of secobarbital or pentobarbital for 6 weeks or longer. Upon abrupt discontinuation, apprehension, uneasiness, muscular weakness, coarse tremors, postural hypotension, anorexia, vomiting, and myoclonic jerks occur within the first day and last up to 2 weeks. Grand mal seizures occur within 2-3 days of discontinuation and last as long as 8 days. Delirium is most likely to develop 3-8 days after drug discontinuation and lasts up to 2 weeks. Strategies for management of the barbiturate withdrawal syndrome include transition to an equivalent dose of phenobarbital, determined by either a challenge dose or loading dose procedure.

Gender, Age, and Cultural/Ethnic Considerations

Age, gender, and cultural factors are important considerations for treatment. Deliberate intoxication to achieve a "high" is most likely to be observed in teenagers and individuals in their 20s. Problems associated with sedative-hypnotics are also seen in individuals in their 40s and older who escalate the dose of prescribed medications. Overall, females have a higher risk of abuse than males. Finally, marked variations in prescription patterns (and availability) of this class of substances in different countries have led to different rates of these disorders across cultures.

Stimulant-Related Disorders

Epidemiology

Stimulant-related disorders encompass the use of amphetamine-type stimulants such as METH, cocaine, recent synthetic stimulant cathinone derivatives ("bath salts"), and compounds of plant origin (cocaine, ephedra, and khat). In this section, we focus on METH, AMPH, and cocaine. Stimulant use disorders (Box 23-23) greatly impact the health care system. In the 2011 National Survey on Drug Use and Health, stimulant use disorders accounted for 14% (cocaine 8%, METH/AMPH 6%) of all patients who entered treatment programs (Substance Abuse and Mental Health Services Administration 2012b). In patients ages 21 years and older, the most common illicit drug involved in drug-related emergency department (ED) visits was cocaine. A more troubling trend is the nearly 200% increase in ED visits due to pharmaceutical stimulants (attention-deficit/hyperactivity [ADHD] medications) from 2004 to 2010 (Substance Abuse and Mental Health Services Administration 2012a).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

There are two forms of cocaine: pure salt (cocaine hydrochloride), which can be injected intravenously, and base (i.e., free-base), which is usually smoked. The. free-base form of cocaine is the most common; because it produces an audible cracking noise when smoked, it is commonly called "crack." METH hydrochloride ("speed," "meth") is usually in powder form and can be inhaled, injected intravenously, or taken orally. A pure crystalline form of the D-isomer is often referred to as "crystal METH" because of its white appearance and assumed purity. A racemic mixture of the L- and D-isomers, which is less potent than the pure D-isomer and often tainted brown-yellow, is called "crank." A highly pure smokable form of the drug is called "ice." Diverted prescription medications used to treat certain disorders (ADHD, narcolepsy) typically contain dexamphetamine.

Intoxication

The half-lives of cocaine and METH differ significantly (cocaine: 40-90 min; METH: 10-12 hours) and contribute to the drugs' effects on intake frequency and toxicity, although individuals intoxicated with either drug share similar symptoms upon clinical presentation (Box 23-24). METH stimulates the central and sympathetic nervous systems and induces euphoria, increased energy, and hypersexuality. Hypersexuality, which leads to loss of sexual inhibition and an increase in risktaking behavior, is more evident with METH than with other stimulants. Psychosis linked to chronic METH consumption resembles paranoid schizophrenia, in that the individuals may experience auditory, visual, and tactile hallucinations, as well as delusions that can be sustained. Chronic METH use increases the incidence of depression, suicidal ideation, and overdose-related mortality. Age at onset of regular use, genetic susceptibility, and environmental stressors are factors that may predispose an individual to develop psychosis. Psychosis and paranoia secondary to high-dose cocaine binge administration may also relate to psychiatric predisposition.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Withdrawal

Withdrawal symptoms following cessation of either cocaine or METH/AMPH use can result in a wide range of dysphoric symptoms (Box 23-25). U may initially experience a "crash" period characterized by anxiety agitation, depression, and later intense drug craving. The time course is influenced by the amount and frequency of drug intake, the half-life of the particular stimulant ingested, and the use history. Individuals undergoing METH/AMPH withdrawal often exhibit a syndrome-like condition, which includes depression, anhedonia, irritability, and poor concentration; this condition usually resolves over days to a few weeks (Newton et al. 2004). Cocaine withdrawal is usually more abrupt but may also produce symptomatology similar to that from METH/AMPH withdrawal. The Cocaine Selective Severity Assessment (CSSA; Kampman et al. 1998) is an 18-item diagnostic instrument that is useful for rating signs and symptoms (0 = no symptoms; 7=maximum severity) and quantifying withdrawal severity (Table 23-16). Cocaine withdrawal symptom severity has been shown to predict subsequent response to treatment (Poling et al. 2007).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Source. Kampman et al. 1998.

Diagnosis

Although no specific tests are available to diagnose stimulant use disorder, certain diagnostic indicators may help rule out other medical conditions. Urine benzoylecgonine, a metabolite of cocaine, is detectable for about 1-3 days following the last dose and may be present longer in individuals who have ingested high doses. Elevated liver function tests may indicate intravenous cocaine use in combination with alcohol. Altered electroencephalogram, prolactin secretion, and decreased dopamine D₂ receptor levels are associated with cocaine dependence. Urine tests for METH/AMPH are useful and may more readily detect use days after consumption of the drug due to the long half-life. Use can be detected for up to 90 days using hair analysis. Other laboratory findings, as well as physical examination and medical conditions linked to chronic cocaine and amphetamine-type stimulant use disorder (weight loss, malnutrition, poor hygiene), help secure the diagnosis.

Treatment

Although some behavioral therapeutic strategies show promise, there are currently no indicated pharmacotherapies for stimulant dependence (Haile et al. 2012b; Kosten et al. 2011). Several medications have been assessed with limited success (Table 23-17). A number of studies have shown that disulfiram, a medication indicated for alcohol use disorder, decreases cocaine use in a variety of patient populations. The therapeutic effects of disulfiram, however, appear to depend on genetic profile (Kosten et al. 2013) and dose (Haile et al. 2012a). A promising line of research has found that antihypertensive medications such as doxazosin (Newton et al. 2012) and perindopril (Newton et al. 2010) block the positive subjective effects and desire for cocaine and METH. These medications have a number of advantages; namely, they have no abuse liability and they confer protection from adverse cardiovascular effects of stimulants. Recent studies indicate that the cholinesterase inhibitor rivastigmine also decreases the likelihood of METH use in individuals with METH use disorder (De La Garza et al. 2012). Modafinil, a medication indicated for the treatment of narcolepsy, and N-acetylcysteine, the treatment for acetaminophen toxicity, have both shown promising therapeutic potential for cocaine dependence in select populations (Haile et al. 2012b). Clinical trials are ongoing.

Psychosocial Treatments

Recent evidence from randomized clinical trials has demonstrated the efficacy of behavioral therapies for stimulant use disorder. Two approaches most extensively investigated are cognitive-behavioral therapy and contingency management. These therapies are associated with modest increases in treatment retention and reductions in cocaine and METH use.

Medical Complications

Cocaine and METH/AMPH have profound effects on the cardiovascular system, resulting in serious complications that are often lethal. Cocaine use is associated with myocardial ischemia and infarction, cardiomyopathy, myocarditis, arrhythmias, endocarditis, and aortic dissection. Within the first hour after cocaine intake, patients increase their risk of having a myocardial infarction (MI) by 24 times. Chest pain is commonly experienced by cocaine users who present to emergency departments and is associated with acute MI in upwards of 6% of these patients. Obstructive coronary artery disease was found in 35%-40% of patients who experienced cocaine-induced chest pain and underwent diagnostic angiography (Dressier et al. 1990). Coronary vasoconstriction, increased myocardial oxygen demand, and thrombus formation may contribute to cocaine-induced MI. Cocaine also prolongs the QTc interval by inhibiting repolarization and can induce ventricular arrhythmias that may or may not be associated with myocardial cell death. Significant increases in peripheral catecholamines following cocaine ingestion lead to increased cardiac demand and vasoconstriction that is linked to left ventricular dilatation and decreased ejection fraction. Abnormal thickening of the atrioventricular node artery, perinodal fibrosis, and chronic inflammatory infiltration resulting in compromised conduction have all been identified in cocaine-induced fatalities.

Adulterants used to dilute cocaine to increase volume for subsequent sales may have adverse effects on health. Common adulterants include sugar; baking soda; anesthetics such as lidocaine and benzocaine; other stimulants such as caffeine; and/or medications such as diltiazem, paracetamol, hydroxyzine, and phenacetin, an analgesic known to be carcinogenic. Levamisole, an antihelminthic drug associated with agranulocytosis and responsible for numerous hospitalizations and deaths, is found in nearly 70% of seized cocaine entering the United States (Czuchlewski et al. 2010).

Note. ACE = angiotensin-converting enzyme; Ca=calcium; DA=dopamine; DAT=dopamine transporter; GABA=γ-aminobutyric acid; MDMA = 3,4-methylenedioxymethamphetamine (Ecstasy); Na=sodium; NE=norepinephrine; NET=norepinephrine transporter.

METH use is associated with significant cardiac toxicity due to sympathetic nervous system overactivation. METH-induced activation leads to hypertension, autonomic nervous system dysfunction associated with MI, and coronary artery disease. In one study, echocardiographic findings indicated that patients younger than age 45 with a history of METH use had more severe dilated cardiomyopathy than those who had not used METH (Ito et al. 2009). Cerebrovascular pathology such as ischemic stroke and intracerebral and subarachnoid hemorrhage caused by METH use is common in young patients. METH has adverse effects on oral health ("meth mouth") such as gum disease, tooth decay due to the toxic smoke, and bruxism while intoxicated.

Route of administration may relate to specific medical complications. Intranasal administration ("snorting") is often associated with epistaxis, perforated nasal septum, and sinusitis. Cocaine and METH/AMPH users are at increased risk of experiencing respiratory problems from smoking and acquiring diseases such as HIV through intravenous injection. Individuals who use METH in particular are more likely to engage in high-risk sexual behavior and become infected with sexually transmitted diseases.

Gender, Age, and Cultural/Ethnic Considerations

Among individuals who inject, males are more likely to be diagnosed with stimulant use disorder than females, but the gender difference is smaller among those who do not inject. Although stimulant use is seen in all age groups, it is more common in individuals younger than age 45 years. Treatment admission data for 2010 indicate that males accounted for 57% of smoked cocaine (average age 41 years) and 68% of nonsmoked cocaine (average age 36 years). Among cocaine smokers, 53% were non-Hispanic blacks and 35% were non-Hispanic whites. The average age of patients admitted for METH/AMPH use disorder was 33 years, with males predominating (53%). In contrast to cocaine, 68% of primary METH/AMPH users were non-Hispanic whites, with Hispanics being the next largest represented ethnic group (19%) (Substance Abuse and Mental Health Services Administration 2012a).

Tobacco-Related Disorders

Epidemiology

In 2010, an estimated 69.6 million Americans ages 12 and older were current (past month) users of a tobacco product (Substance Abuse and Mental Health Services Administration 2010). This represents 27.4% of the population in that age range. Of these, 58.3 million smoked cigarettes, 13.2 million smoked cigars, 8.9 million used smokeless tobacco, and 2.2 million smoked tobacco in pipes. The highest prevalence rates of smoking are among those ages 21-25 years (37.7%), with those ages 18-20 years (33.1%) following closely behind. Developing treatments for younger smokers is an important goal given that 1) a majority of those who become regular smokers early in life continue to do so into adulthood and 2) the likelihood of developing smoking-related cancers increases with smoking duration. The DSM-5 criteria for tobacco use disorder are presented in Box 23-26.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Importantly, use of illicit drugs and alcohol was more common among current cigarette smokers than among nonsmokers in 2010, as in prior years since 2002 (Substance Abuse and Mental Health Services Administration 2010). Among individuals ages 12 years and older, 22.6% of past-month cigarette smokers reported current use of an illicit drug, compared with 4.9% of individuals who were not current cigarette smokers. More than half (52.9%) of youths ages 12-17 years who smoked cigarettes in the past month also used an illicit drug, compared with 6.2% of youths who did not smoke cigarettes (Substance Abuse and Mental Health Services Administration 2010).

Intoxication and Withdrawal

Like other drugs of abuse, nicotine is highly reinforcing and has considerable addictive potential. Nicotine exposure increases DA in the NAc. Nicotine's effects are mediated by nicotinic acetylcholine receptors (nAChRs), which are present on mesolimbic DA neurons. Stimulation of nAChRs augments DA release and metabolism (George et al. 1998), and repeated nicotine exposure functionally increases nAChRs and sensitization of the mesolimbic DA response to nicotine. Nicotine withdrawal effects include irritability, difficulty concentrating, and depressed mood, among others (Box 23-27).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Diagnosis

Diagnosis of nicotine use disorder is made according to DSM-5 criteria, yet other rating scales that may be useful include the Fagerström Test for Nicotine Dependence (Heatherton et al. 1991; Figure 23-5). This test may be helpful in guiding therapy because the number of cigarettes smoked per day is negatively correlated with success in quitting and treatment response.

Treatment

Most smokers report wanting to quit smoking and most try to quit on their own. However, only 3%-5% of smokers who try to quit unaided maintain their quit attempts 1 year later, and the majority relapse within the first 8 days of the quit attempt. First-line pharmacotherapies for nicotine dependence include nicotine-replacement therapy, bupropion, and varenicline (Table 23-18). These treatments generally double the chance of quitting smoking. Notwithstanding, rates of abstinence are still only 20%-33% at 6 months (Fiore et al. 2008), suggesting an important role for behavior-based treatments for smoking cessation.

Promising psychosocial treatments for smoking cessation include cognitive-behavioral therapy (CBT) and contingency management (CM). CBT helps individuals recognize situations in which they are likely to use drugs, how to avoid such situations, and how to cope with drug cravings when avoiding cues is not possible. A previous meta-analysis established the efficacy of CBT in over 24 randomized controlled trials among adults with substance dependence, and CBT appears to be particularly effective in treating nicotine dependence. CM is an evidence-based treatment providing differential rewards contingent on meeting various treatment goals such as drug abstinence. Many of the individual benefits of quitting smoking are temporally distant (e.g., improved health, financial savings) and may be difficult to discriminate for the individual trying to quit. CM helps bridge this temporal gap by providing relatively immediate rewards for smoking abstinence and has been demonstrated to be an effective treatment for cigarette smoking. Although both CM and CBT have been demonstrated to be effective, common criticisms of these treatments include frequent visits to the clinic and greater demand on resources such as the clinician's time. However, recent advances such as computerized CBT and Internet-based CM illustrate that technological innovation can answer such criticisms while increasing the efficacy of these treatments.

Figure 23-5. Fagerström Test for Nicotine Dependence.

Source. Adapted from Heatherton et al. 1991.

Note. The information contained within this table is not comprehensive. Please see package inserts for the individual medications for additional information. OTC=over the counter.

Source. www.fda.gov/Drugs.

Medical Complications

Cigarette smoking is the leading preventable cause of death and morbidity in the United States. Smoking directly contributes to 1 of every 5 deaths in the United States each year (nearly half a million); which is more than all the deaths caused by HIV, illegal drug use, problem alcohol use, motor vehicle injuries, suicides, and murders combined. Smoking is responsible for approximately 4 of 5 cases of lung cancer, which is the most common cause of cancer death (American Cancer Society 2012). Among those not killed by smoking cigarettes, 8.6 million cigarette smokers in the United States live with a serious smoking-related illness (e.g., emphysema, high blood pressure).

Importantly, passive or secondary smoke also increases the risk for many diseases. In fact, approximately 3,400 lung cancer deaths and 46,000 deaths from coronary heart disease occur per year among exposed nonsmokers (American Cancer Society 2012).

Chewing tobacco and snuff contain dozens of carcinogens. Not surprisingly, smokeless tobacco increases the risk for cancer of the oral cavity, which can include cancer of the lips, tongue, cheeks, gums, and floor and roof of the mouth. Other effects include oral leukoplakia, gum disease, and gum recession.

Gender, Age, and Cultural/Ethnic Considerations

In 2010, current use of a tobacco product among persons ages 12 and older was reported by a higher percentage of males (33.7%) than females (21.5%). Males also had higher rates of past month use of each specific tobacco product: cigarettes (25.4% of males vs. 20.7% of females), cigars (8.5 vs. 2.1%), smokeless tobacco (6.8 vs. 0.4%), and pipe tobacco (1.4 vs. 0.3%). In 2010, the prevalence of current use of a tobacco product among persons ages 12 and older was 12.5% for Asians, 21.9% for Hispanics, 27.3% for blacks, 29.5% for whites, 32.0% for persons who reported two or more races, and 35.8% for American Indians or Alaska Natives (Substance Abuse and Mental Health Services Administration 2010).

Other (or Unknown) Substance-Related Disorders

The other (or unknown) substance-related disorders diagnostic class encompasses substance-related disorders unrelated to the main substance classes previously discussed in this chapter (e.g., alcohol, cannabis, opioids). Included in this category are unknown intoxicants and unidentified designer synthetic compounds (e.g., derivatives of cathinone or "bath salts" and cannabinoids or "spice") sold on the black market. Known substances in this category include amyl-, butyl-, and isobutyl nitrite gases; anabolic steroids; cortisol; antiMstamines; medications for Parkinson's disease; and substances of plant origin such as betel nut and khat (source of natural cathinone, a stimulant). If the substance is known, it should be identified in the disorder name (e.g., anabolic steroid use disorder, antihistamine use disorder). As with other substance use disorders, use of the known or unknown substance continues even though serious psychiatric and/or physical problems develop.

Epidemiology

The prevalence of other (or unknown) substance use disorder (Box 23-28) is probably lower than that of the other substance use disorders. If the substance in question can be identified, then available statistics may be accessed. Regarding "bath salts" and "spice-like" substances, exposure rates are monitored by poison control centers; however, proper identification requires analytical toxicology methods (American Association of Poison Control Centers 2013; Meyer and Peters 2012). Packages of these substances may contain many different derivatives yet are referred to by those general terms. The U.S. Drug Enforcement Administration has designated five known "spice-like" compounds provisional schedule I status (JWH-018, JWH-073, JWH-200, CP-47,497) whereas "bath salts" mephedrone (also called "meow meow"), methylone, and 3,4-methylene-dioxypyrovalerone (MDPV) have schedule I status. Prevalence estimates suggest that 2% of adolescent and college-age individuals and upwards of 50% of weight lifters use anabolic steroids (Dodge and Hoagland 2011). New analytic detection methods are required to identify unique designer steroid compounds intended to evade discovery (Teale et al. 2012).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Intoxication and Withdrawal

Other (or unknown) substance intoxication (Box 23-29) develops following use of a substance that does not fall within the nine substance classes or is an unknown substance. As noted previously with diagnosing a substance use disorder, if the substance is known, the diagnosis of substance intoxication should be reflected in the name (e.g., khat intoxication). An intoxication syndrome that is reversible following ingestion of another (or unknown) substance, clinically significant behavioral or psychological changes attributed to the substance and not to another medical or psychiatric condition or another substance are diagnostic criteria for other (or unknown) substance intoxication.

The adverse effects of novel unknown compounds are often first identified through emergency department admissions. Diagnosis of substance intoxication is further complicated by polysubstance users exhibiting numerous symptoms characteristic of different substance classes (Thornton et al. 2012). Information from the individual confirming similar symptoms following consuming the substance on other occasions, from the same source, in addition to information from emergency departments may help recognize a newly available substance.

Intoxication following administration of a given substance is influenced by pharmacokinetics, pharmacodynamics, and substance toxicity, route of administration and even substance use history of the individual (e.g., tolerance). Generally, following substance administration, intoxication is characterized by increasing physiological and subjective effects that peak then decrease over time. The temporal characteristics of intoxication are usually substance-specific for a given class.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Withdrawal symptoms are substance-specific and range from brief discomfort such as headache (caffeine) to severe, life-threatening medical and psychiatric consequences such as seizures (alcohol, barbiturates, benzodiazepines), psychosis, and depression (methamphetamine). Key features of other (or unknown) substance withdrawal (Box 23-30) include onset of symptoms following reduction in use or elimination of consumption of a substance that is not listed under any of the nine substance categories or that is unknown.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Diagnosis

Diagnosis of other (or unknown) substance use disorder relies upon the following: 1) the individual reports that the substance used is not included within the nine substance classes, 2) repeated exposure to the substance is associated with an intoxication syndrome, 3) results of standard drug screens are negative, and 4) there is corroboration within the individual's community that similar intoxication symptoms following use of the substance have occurred. Novel substances that cannot be identified on routine drug screens may be identified using specialized analytical toxicology assays (Meyer and Peters 2012).

Medical Complications

An extensive array of medical consequences may result following acute or chronic administration of an other (or unknown) substance. Previously unknown or strange unfamiliar cases presented at emergency departments may signal novel substance use (Harris and Brown 2013; Thornton et al. 2012). Adverse medical consequences of a given substance may manifest through action on systems other than the CNS. For example, a recent report from the Centers for Disease Control and Prevention (2013) noted acute kidney injury following smoked synthetic cannabinoids; substances identified only a few years ago. Extensive reviews have also linked chronic betel nut/betel quid use with oral and oropharyngeal cancers (Sharan et al. 2012). Furthermore, performance enhancing anabolic steroids are often used in combination with cocaine or METH/AMPH that is associated with significant effects on cardiovascular health (Angell et al. 2012; Dodge and Hoagland 2011). Acute administration of khat results in prototypical stimulant effects (e.g., euphoria, increased sympathetic activation) and increased risk of an adverse cardiovascular event such as myocardial infarction or stroke as well as psychosis (Ali et al. 2010; Odenwald et al. 2005). In general, the physical and psychiatric effects of "bath salts" also mimic other stimulants (Miotto et al. 2013). Clinical judgment is fundamental to proper medical management.

Gender, Age, and Cultural/Ethnic Considerations

Gender, age, and other prognostic factors for other (or unknown) substance use disorders may be similar to other substance use disorders with the exception of those substances that are specific to a given culture. For example, betel nut (areca nut) or betel quid is a stimulant—often chewed with tobacco (called paan and gutka)—that is used by an estimated 600,000 million people worldwide, predominantly in Asian countries; however, the numbers are increasing in immigrant communities within the United States (Banerjee et al. 2013; Lee et al. 2011). The leaves, or khat, from the tree Catha edulis contain alkaloids (primarily cathinone) that have stimulant properties (Hoffman and Al'Absi 2010). Use is very high in some African and Asian countries (males > 80%; females > 10%) (Numan 2004; Odenwald et al. 2005). Data on khat use is scarce; however, immigrant communities in Europe, and presumably in the United States, composed of individuals from countries where khat is common show robust demand (Griffiths et al. 2010). Factors associate with other substance use disorders are presumed to apply to other (or unknown) substance use and related disorders such as childhood substance use, childhood psychological or physical trauma, presence of other substance use disorders in the individual or family, lack of impulse control, conduct disorder and antisocial personality disorder, and substance availability.

Non-Substance-Related Disorders

Gambling Disorder

Epidemiology

DSM-5 has renamed "pathological gambling," gambling disorder which is now listed along with substance-related disorders (Box 23-31). The rationale for this reclassification is based on evidence from clinical studies indicating that problem gamblers share brain abnormalities and behavioral characteristics commonly seen in individuals with substance use disorder (Leeman and Potenza 2012). Indeed, gambling disorder is often referred to as an addiction without the drug (Potenza 2013). Epidemiological survey data also indicate high rates of co-occurrence for substance use disorder and gambling disorder. Estimates of lifetime risk of an individual with gambling disorder developing a substance use disorder range from 35% to 63% (Grant et al. 2010). Overall, estimates of lifetime prevalence of gambling disorder among adults in the United States range from approximately 0.4% to 1.6% but are significantly influenced by a number of factors (Shaffer et al. 1999; Westermeyer et al. 2013).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Diagnosis

Persistent and recurrent maladaptive gambling behavior that disrupts personal, family, and/or occupational pursuits is a key characteristic of gambling disorder. The individual may gamble with increasing amounts of money to become excited. The placing of larger bets or increasing risk to make back money for previous losses ("chasing one's losses") is a common behavioral pattern in individuals with gambling disorder. Individuals with gambling disorder may have endured unsuccessful efforts to control cut back or stop gambling, are preoccupied with gambling and gamble when feeling distressed.

Other problem behaviors associated with gambling disorder involve lying about gambling, negative effects on personal, educational or occupational opportunity and relying on others for financial support ("bailout") due to gambling. Inaccurate and distorted thinking in individuals with gambling disorder may involve denial, superstitions, overconfidence and a sense of control over outcomes from gambling. Impulsivity, compulsivity or a general lack of self-control are key characteristics associated with gambling disorder that has been linked to deficits in the frontal cortex (Leeman and Potenza 2012; Potenza 2013). Co-occurring psychiatric disorders are common in individuals who also have gambling disorder (Petry et al. 2005).

Treatment

Clinical trials have assessed the effectiveness of a number of behavioral therapies as treatments for gambling disorder. A recent meta-analysis that included 14 studies (N=1,245) concluded that the best available evidence supports cognitive behavioral therapy for gambling disorder.

Although there are no FDA-approved pharmacotherapies for gambling disorder, medications used to treat other substance use disorders have shown promise. Results from short-term clinical trials appear to support naltrexone—which is indicated to treat alcohol and opioid use disorders—as a potential therapy for gambling disorder (Grant et al. 2012). Furthermore, in a 4-year follow-up study in patients with gambling disorder treated with one of four medications (naltrexone, topiramate, bupropion, and escitalopram), naltrexone was found to be most effective (Rosenberg et al. 2013).

Medical Complications

Gambling disorder is associated with poor overall health and co-occurring medical and psychiatric conditions (Morasco et al. 2006; Petry et al. 2005; Pilver et al. 2013b).

It is clear that DA release within the ventral striatum plays a major role in the reinforcing effects of all substances implicated in use disorders, and this also applies to gambling disorder (Joutsa et al. 2012). Accumulating evidence implicates DA agonist medications used to treat Parkinson's disease contributing to the development of gambling disorder. Indeed/the prevalence of gambling disorder among those with Parkinson's disease is significantly higher (upwards of 8%) compared with the general population (Santangelo et al. 2013; Weintraub et al. 2010). Taken together, these findings suggest that gambling disorder in individuals with Parkinson's disease may relate to DA agonist therapy (e.g., pramipexole, ropinirole) (Weintraub et al. 2010).

Gender, Age, and Cultural/Ethnic Considerations

In general, gambling disorder is more common among males than females across all age groups. Males are more likely to start gambling earlier and develop gambling disorder at a younger age and at higher rates than females. Regarding substance use disorders, studies suggest problematic gambling is associated with nicotine use disorder in women and alcohol use disorder in men (Pilver et al.

2013a). Estimated prevalence rates of gambling disorder among college students is ten times that of the general population (Nowak and Aloe 2013). Gambling disorder is also more prevalent among African Americans, American Indians and veterans (Westermeyer et al. 2013).

Key Clinical Points

• DSM-5 designates substance-related disorders as a global term that is divided into substance use and substance-induced disorders focused on nine drug classes: alcohol; caffeine; cannabis; hallucinogens; inhalants; opioids; sedatives, hypnotics, and anxiolytics; stimulants (cocaine and amphetaminelike drugs); and tobacco.
• According to the global health status report by the World Health Organization (2011a), approximately 4.5% of the global burden of disease and injury is attributable to alcohol, and tobacco use continues to be the leading global cause of preventable death.
• Physicians should inquire about all classes of substances, legal and illegal, including prescription medications, because a patient may not regard abuse of some substances to be as significant as that of others.
• Psychosocial and behavioral approaches are the cornerstones of treatment for substance-related disorders, yet medications are increasingly being used to augment the treatment. Recent advances in development of medications for the treatment of stimulant dependence appear promising.
• There are currently four medications with FDA approval for the maintenance treatment of alcohol dependence: disulfiram, oral naltrexone, a long-acting intramuscular formulation of naltrexone, and acamprosate.
• About 1.4 million youths ages 12-17 years were current marijuana users in 2011, and the number of daily users among this age group rose sharply from 2009 to 2011.
• The use of buprenorphine for detoxification or maintenance treatment in opioid dependence is increasingly common, in part because buprenorphine can be prescribed in a physician's office with up to 1 month's prescription at a time.
• Use of multiple substances is common; among persons ages 12 years and older, 22.6% of past month cigarette smokers reported current use of an illicit drug, compared with 4.9% of persons who were not current cigarette smokers.
• Treatment for tobacco use disorder generally doubles the chance of quitting; however, abstinence rates are still only 20%-33% at 6 months.
• Substance-related disorders and other psychiatric disorders commonly cooccur. This relationship is complex and likely influenced by genetic background.
• The recent increase in the rates of nonmedical use of prescription stimulants and pain killers (specifically opioids) and designer cannabinoid-like compounds in adolescents is notable and troubling.

References

American Association of Poison Control Centers: Human exposure calls to poison centers about bath salts and synthetic marijuana, 2013. Alexandria, VA, American Association of Poison Control Centers, 2013. Available at: http://www.aapcc.org. Accessed October 1, 2013.

Ali WM, Zubaid M, Al-Motarreb A, et al: Association of khat chewing with increased risk of stroke and death in patients presenting with acute coronary syndrome. Mayo Clin Proc 85:974-980, 2010

American Cancer Society: Cancer Facts and Figures 2012. Available at: www.can-cer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-fig-ures-2012. Accessed September 7, 2012.

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Arlington, VA, American Psychiatric Association, 2013

Angell PJ, Chester N, Sculthorpe N, et al: Performance enhancing drug abuse and cardiovascular risk in athletes: implications for the clinician. Br J Sports Med 46 (suppl l):i78—i84, 2012

Babor TF, Higgins-Biddle JC, Saunders JB, et al: The Alcohol Use Disorders Identification Test: Guidelines for Use in Primary Care, 2nd Edition. Geneva, Department of Mental Health and Substance Dependence, World Health Organization, 2001

Banerjee SC, Ostroff JS, Bari S, et al: Gutka and tambaku paan use among South Asian immigrants: a focus group study. J Immigr Minor Health. 2013 Apr 12. [Epub ahead of print]

Blanck HM, Serdula MK, Gillespie C, et al: Use of nonprescription dietary supplements for weight loss is common among Americans. J Am Diet Assoc 107:441-447, 2007

Bouchery EE, Harwood HJ, Sacks JJ, et al: Economic costs of excessive alcohol consumption in the U.S., 2006. Am J Prev Med 41:516-524, 2011

Bryant AN, Kim G: Racial/ethnic differences in prevalence and correlates of binge drinking among older adults. Aging Ment Health 16:208-217, 2012

Bryson WC, McConnell J, Korthuis PT, et al: Extended-release naltrexone for alcohol dependence: persistence and healthcare costs and utilization. Am J Manag Care 17 (suppl 8):S222-S234, 2011

Budney AJ, Vandrey RG, Hughes JR, et al: Comparison of cannabis and tobacco withdrawal: severity and contribution to relapse. J Subst Abuse Treat 35:362-368, 2008

Carroll KM, Ball SA, Martino S, et al: Enduring effects of a computer-assisted training program for cognitive behavioral therapy: a 6-month follow-up of CBT4CBT. Drug Alcohol Depend 100:178-181, 2009

Centers for Disease Control and Prevention: Fact Sheets: Alcohol Use and Health—Alcohol, 2012. Available at: www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm. Accessed August 7, 2012.

Centers for Disease Control and Prevention: Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012. MMWR Morb Mortal Wkly Rep 62:93-98, 2013

Clapper JR, Mangieri RA, Piomelli D: The en-docannabinoid system as a target for the treatment of cannabis dependence. Neuropharmacology 56 (suppl):235-243, 2009

Collins ED, Kleber HD: Opioids: detoxification, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 3rd Edition. Edited by Galanter M, Kleber HD. Washington, DC, American Psychiatric Publishing, 2004, pp 265-289

Cottier LB, Leung KS, Abdallah AB: Test-retest reliability of DSM-IV adopted criteria for 3,4-methylenedioxymethamphetamine (MDMA) abuse and dependence: a cross-national study. Addiction 104:1679-1690, 2009

Czuchlewski DR, Brackney M, Ewers C, et al: Clinicopathologic features of agranulocytosis in the setting of levamisole-tainted cocaine. Am J Clin Pathol 133:466-72, 2010

Daley DC, Marlatt GA: Overcoming Your Alcohol or Drug Problem: Effective Recovery Strategies Workbook. New York, Oxford University Press, 2006

De La Garza R 2nd, Newton TF, Haile CN, et al: Rivastigmine reduces "Likely to use methamphetamine" in methamphet-amine-dependent volunteers. Prog Neuropsychopharmacol Biol Psychiatry 37:141-146, 2012

Dodge T, Hoagland MF: The use of anabolic androgenic steroids and polypharmacy: a review of the literature. Drug Alcohol Depend 114:100-109, 2011

Dong C, Yoon Y-H, Chen CM, et al: Heavy alcohol use and premature death from hepatocellular carcinoma in the United States, 1999-2006. J Stud Alcohol Drugs 72:892-902, 2011

Donovan DM, Anton RF, Miller WR, et al: Combined pharmacotherapies and behavioral interventions for alcohol dependence (The COMBINE Study): examination of posttreatment drinking outcomes. J Stud Alcohol Drugs 69:5-13, 2008

Dressier FA, Malekzadeh S, Roberts WC: Quantitative analysis of amounts of coronary arterial narrowing in cocaine addicts. Am J Cardiol 65:303-308, 1990

Eng MY, Luczak SE, Wall TL: ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review. Alcohol Res Health 30:22-27, 2007

Ewing JA: Detecting alcoholism: the CAGE questionnaire. JAMA 252:1905-1907, 1984

Feigelman W, Gorman BS: Prospective predictors of premature death: evidence from the National Longitudinal Study of Adolescent Health. J Psychoactive Drugs 42:353-361, 2010

Fiore M, Jaen C, Baker T, et al: A clinical practice guideline for treating tobacco use and dependence: 2008 update. A U.S. Public Health Service report. Am J Prev Med 35:158-176, 2008

George TP, Verrico CD, Roth RH: Effects of repeated nicotine pre-treatment on mesoprefrontal dopaminergic and behavioral responses to acute footshock stress. Brain Res 801:36-49, 1998

Goldstein RZ, Volkow ND: Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 12:652-669, 2011

Grant JE, Potenza MN, Weinstein A, et al: Introduction to behavioral addictions. Am J Drug Alcohol Abuse 36:233-241, 2010

Grant JE, Odlaug BL, Schreiber LR: Pharmacological treatments in pathological gambling. Br J Clin Pharmacol. 2012

Sep 14. [Epub ahead of print]

Griffiths P, Lopez D, Sedefov R, et al: Khat use and monitoring drug use in Europe: the current situation and issues for the future. J Ethnopharmacol 132:578-583, 2010

Gueorguieva R, Wu R, Donovan D, et al: Naltrexone and combined behavioral intervention effects on trajectories of drinking in the COMBINE study. Drug Alcohol Depend 107:221-229, 2010

Haile CN, De La Garza R 2nd, Mahoney JJ 3rd, et al: The impact of disulfiram treatment on the reinforcing effects of cocaine. PloS One 7:e47702, 2012a

Haile CN, Mahoney JJ 3rd, Newton TF, et al: Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: focus on dopamine, norepinephrine and glutamate. Pharmacol Ther 134:260-277, 2012b

Halberstadt AL, Geyer MA: Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology 61:364-381, 2011

Halpern JH, Sherwood AR, Hudson JI, et al: Psychological and cognitive effects of long-term peyote use among Native Americans. Biol Psychiatry 58:624-631, 2005

Haney M, Hart CL, Vosburg SK, et al: Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacology 29:158-170, 2004

Haney M, Bedi G, Cooper ZD, et al: Predictors of marijuana relapse in the human laboratory: robust impact of tobacco cigarette smoking status. Biol Psychiatry 73:242-248, 2013

Harris CR, Brown A: Synthetic cannabinoid intoxication: a case series and review. J Emerg Med 44:360-366, 2013

Heatherton TF, Kozlowski LT, Frecker RC, et al: The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict 86:1119-1127, 1991

Hester RK, Squires DD, Delaney HD: The Drinker's Check-Up: 12-month outcomes of a controlled clinical trial of a stand-alone software program for problem drinkers. J Subst Abuse Treat 28:159-169, 2005

Hietala J, Koivisto H, Anttila P, et al: Comparison of the combined marker GGT-CDT and the conventional laboratory markers of alcohol abuse in heavy drinkers, moderate drinkers and abstainers. Alcohol Alcohol 41:528-533, 2006

Higgins ST, Silverman K, Heil SH (eds): Contingency Management in Substance Abuse Treatment. New York, Guilford, 2008

Hoffman R, Al'Absi M: Khat use and neurobehavioral functions: suggestions for future studies. J Ethnopharmacol 132:554-563, 2010

Howard MO, Bowen SE, Garland EL, et al: Inhalant use and inhalant use disorders in the United States. Addict Sci Clin Pract 6:18-31, 2011

Hughes JR, Oliveto AH, Liguori A, et al: Endorsement of DSM-IV dependence criteria among caffeine users. Drug Alcohol Depend 52:99-107, 1998

Ito H, Yeo K-K, Wijetunga M, et al: A comparison of echocardiographic findings in young adults with cardiomyopathy: with and without a history of methamphetamine abuse. Clin Cardiol 32:E18-E22, 2009

Jørgensen CH, Pedersen B, Tonnesen H: The efficacy of disulfiram for the treatment of alcohol use disorder. Alcohol Clin Exp Res 35:1749-1758, 2011

Joutsa J, Johansson J, Niemelä S, et al: Meso-limbic, dopamine release is linked to symptom severity in pathological gambling. Neuroimage 60:1992-1999, 2012

Juliano LM, Griffiths RR: A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl) 176:1-29, 2004

Kampman KM, Volpicelli JR, McGinnis DE, et al: Reliability and validity of the Cocaine Selective Severity Assessment. Addict Behav 23:449-461, 1998

Kerridge BT, Saha TD, Smith S, et al: Dimensionality of hallucinogen and inhalant/solvent abuse and dependence criteria: implications for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Addict Behav 36:912-918, 2011

Klingemann H, Sobell LC (eds): Promoting Self-Change From Addictive Behaviors: Practical Implications for Policy, Prevention, and Treatment. New York, Springer Science + Business Media, 2007

Kosten TR, Newton TF 2nd, De La Garza R 2nd, Haile CN: Cocaine and Methamphet-amine Dependence: Advances in Treatment. Washington, DC, American Psychiatric Publishing, 2011

Kosten TR, Wu G, Huang W, et al: Pharmaco-genetic randomized trial for cocaine abuse: disulfiram and dopamine β-hydroxylase. Biol Psychiatry 73:219-224, 2013

Lee CH, Ko AM, Warnakulasuriya S, et al: Intercountry prevalences and practices of betel-quid use in south, southeast and eastern Asia regions and associated oral preneoplastic disorders: an international collaborative study by Asian betel-quid consortium of south and east Asia. Int J Cancer 129:1741-1751, 2011

Leeman RF, Potenza MN: Similarities and differences between pathological gambling and substance use disorders: a focus on impulsivity and compulsivity. Psychopharmacology (Berl) 219:469-490, 2012

Marsolek MR, White NC, Litovitz TL: Inhalant abuse: monitoring trends by using poison control data, 1993-2008. Pediatrics 125(5):906-913, 2010

Mayfield D, McLeod G, Hall P: The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry 131:1121-1123, 1974

McCrady BS, Epstein EE: Overcoming Alcohol Problems: A Couples Focused Program. Therapist Guide. New York, Oxford University Press, 2009

McLellan AT, Lewis DC, O'Brien CP, et al: Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284:1689-1695, 2000

Mee-Lee D, Shulman MJ, Gastfriend DR, et al: ASAM PPC-2R: Patient Placement Criteria, 2nd Revised Edition, 2012. Available at: www.asam.org/publications/patient-placement-criteria/ppc-2r. Accessed September 9, 2012.

Meyer MR, Peters FT: Analytical toxicology of emerging drugs of abuse—an update. Ther Drug Monit 34:615-621, 2012

Miotto K, Striebel J, Cho AK, et al: Clinical and pharmacological aspects of bath salt use: a review of the literature and case reports. Drug Alcohol Depend 132:1-12, 2013

Mir A, Obafemi A, Young A, et al: Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics 128: el622-el627, 2011

Morasco BJ, Pietrzak RH, Blanco C, et al: Health problems and medical utilization associated with gambling disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Psychosom Med 68:976-984, 2006

National Institute on Alcohol Abuse and Alcoholism: Helping Patients Who Drink Too Much: A Clinician's Guide (NIH Publ No 07-3769). Bethesda, MD, National Institute on Alcohol Abuse and Alcoholism, Updated 2005 Edition. Available at: www.niaaa.nih.gov/publications/clini-cal-guides-and-manuals/helping-patients-who-drink-too-much-clinicians-guide. Accessed September 13, 2013.

National Institute on Drug Abuse: Drug Facts: Marijuana. December 2012. Available at: http://www.drugabuse.gov/sites/default/files/marijuana_0.pdf. Accessed September 13, 2013.

Newton TF, Kalechstein AD, Duran S, et al: Methamphetamine abstinence syndrome: preliminary findings. Am J Addict 13: 248-255, 2004

Newton TF, De La Garza R, Grasing K: The angiotensin-converting enzyme inhibitor perindopril treatment alters cardiovascular and subjective effects of methamphetamine in humans. Psychiatry Res 179:96-100, 2010

Newton TF, De La Garza R 2nd, Brown G, et al: Noradrenergic a(l) receptor antagonist treatment attenuates positive subjective effects of cocaine in humans: a randomized trial. PLoS ONE 7:e30854, 2012

Niemelä O: Biomarkers in alcoholism. Clin Chim Acta 377:39-49, 2007

Nowak DE, Aloe AM: The prevalence of pathological gambling among college students: a meta-analytic synthesis, 2005-2013. J Gambl Stud. 2013 Jul 11. [Epub ahead of print]

Numan N: Exploration of adverse psychological symptoms in Yemeni khat users by the Symptoms Checklist-90 (SCL-90). Addiction 99:61-65, 2004

Odenwald M, Neuner F, Schauer M, et al: Khat use as risk factor for psychotic disorders: a cross-sectional and case-control study in Somalia. BMC Med 3:5, 2005

Pemberton MR, Williams J, Herman-Stahl M, et al: Evaluation of two web-based alcohol interventions in the U.S. military. J Stud Alcohol Drugs 72:480-489, 2011

Petry NM, Stinson FS, Grant BF: Comorbidity of DSM-IV pathological gambling and other psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 66:564-574, 2005

Pilver CE, Libby DJ, Hoff RA, Potenza MN: Gender differences in the relationship between gambling problems and the incidence of substance-use disorders in a nationally representative population sample. Drug Alcohol Depend 133:204-211, 2013a

Pilver CE, Libby DJ, Hoff RA, Potenza MN: Problem gambling severity and the incidence of Axis I psychopathology among older adults in the general population. J Psychiatr Res 47:534-541, 2013b

Poling J, Kosten TR, Sofuoglu M: Treatment outcome predictors for cocaine dependence. Am J Drug Alcohol Abuse 33:191-206, 2007

Potenza MN: Neurobiology of gambling behaviors. Curr Opin Neurobiol 23:660-667, 2013

Rapp C, Bugra H, Riecher-Rossler A, et al: Effects of cannabis use on human brain structure in psychosis: a systematic review combining in vivo structural neuroimaging and postmortem studies. Curr Pharm Des 18:5070-5080, 2012

Riegel AC, Zapata A, Shippenberg TS, et al: The abused inhalant toluene increases dopamine release in the nucleus accumbens by directly stimulating ventral tegmental area neurons. Neuropsychopharmacology 32:1558-1569, 2007

Rietschel M, Treutlein J: The genetics of alcohol dependence. Ann N Y Acad Sci 1282: 39-70, 2013

Rosenberg O, Dinur LK, Dannon PN: Four-year follow-up study of pharmacological treatment in pathological gamblers. Clin Neuropharmacol 36:42-45, 2013

Rösner S, Hackl-Herrwerth A, Leucht S, et al: Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev (12): CD001867, 2010

Russell M, Martier SS, Sokol RJ, et al: Screening for pregnancy risk-drinking. Alcohol Clin Exp Res 18:1156-1161, 1994

Saitz R, Galanter M (eds): Alcohol/Drug Screening and Brief Intervention: Advances in Evidence Based Practice. Binghamton, NY, Haworth Medical Press, 2007

Santangelo G, Barone P, Trojano L, et al: Pathological gambling in Parkinson's disease. A comprehensive review. Parkinsonism Relat Disord 19:645-653, 2013

Satre DD, Chi FW, Mertens JR, et al: Effects of age and life transitions on alcohol and drug treatment outcome over nine years. J Stud Alcohol Drugs 73:459-468, 2012

Schuckit MA: Alcohol-use disorders. Lancet 373:492-501, 2009

Schuckit MA, Smith TL, Trim RS, et al: A prospective evaluation of how a low level of response to alcohol predicts later heavy drinking and alcohol problems. Am J Drug Alcohol Abuse 37:479-486, 2011

Selzer ML: The Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument. Am J Psychiatry 127:1653-1659, 1971

Shaffer HJ, Hall MN, Vander Bilt J: Estimating the prevalence of disordered gambling behavior in the United States and Canada: a research synthesis. Am J Public Health 89:1369-1376, 1999

Sharan RN, Mehrotra R, Choudhury Y, et al: Association of betel nut with carcinogenesis: revisit with a clinical perspective. PLoS One 7:e42759, 2012

Substance Abuse and Mental Health Services Administration: Results from the 2009 National Survey on Drug Use and Health, Vol I: Summary of National Findings. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2010

Substance Abuse and Mental Health Services Administration: The DAWN Report: Highlights of the 2010 Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visits. Rockville, MD, Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, July 2, 2012a. Available at: http://www.samhsa.gov/data/2kl2/DAWN096/SR096EDHighlights2010.pdf. Accessed September 13, 2013.

Substance Abuse and Mental Health Services Administration: Results from the 2011 National Survey on Drug Use and Health: Summary of National Findings (NSDUH Series H-44, HHS Publ No SMA12-4713). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2012b. Available at: http://www.sam-hsa.gov/data/nsduh/2kllresults/nsduhresults2011.htm. Accessed September 13, 2013.

Substance Abuse and Mental Health Services Administration: The TEDS [Treatment Entry Data Set] Report: Marijuana Admissions Reporting Daily Use at Treatment Entry. Rockville, MD, Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, February 2, 2012c. Available at: http://www.samhsa.gov/data/2kl2/TEDS_SR_029_Marijuana_2012/TEDS_Short_Report_029_Marijuana_2012.pdf. Accessed September 13, 2013.

Sullivan J, Sykora K, Schneiderman J, et al: Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 84(11):1353-1357, 1989

Sulzer D: How addictive drugs disrupt pre-synaptic dopamine neurotransmission. Neuron 69:628-649, 2011

Teale P, Scarth J, Hudson S: Impact of the emergence of designer drugs upon sports doping testing. Bioanalysis 4:71-

88, 2012

Thornton SL, Lo J, Clark RF, et al: Simultaneous detection of multiple designer drugs in serum, urine, and CSF in a patient with prolonged psychosis. Clin Toxicol (Phila) 50:1165-1168, 2012

United Nations Office on Drugs and Crime: World Drug Report 2012, Sales No. E.12.XI.1. Vienna, Austria, Research and Trend Analysis Branch, United Nations Office on Drugs and Crime, 2012

Verdejo-Garcia A, Lawrence AJ, Clark L: Impulsivity as a vulnerability marker for substance-use disorders: review of findings from high-risk research, problem gamblers and genetic association studies. Neurosci Biobehav Rev 32:777-810, 2008

Volkow ND, Wang G-J, Fowler JS, et al: Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain's control circuit. Bioessays 32:748-755, 2010

Vonghia L, Leggio L, Ferrulli A, et al: Acute alcohol intoxication. Eur J Intern Med 19:561-567, 2008

Weintraub D, Koester J, Potenza MN, et al: Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 67:589-595, 2010

Westermeyer J, Canive J, Thuras P, et al: Pathological and problem gambling among veterans in clinical care: prevalence, demography, and clinical correlates. Am J Addict 22:218-225, 2013

Witkiewitz K, Saville K, Hamreus K: Acamprosate for treatment of alcohol dependence: mechanisms, efficacy, and clinical utility. Ther Clin Risk Manag 8:45-53, 2012

Wolk BJ, Ganetsky M, Babu KM: Toxicity of energy drinks. Curr Opin Pediatr 24:243-251, 2012

Work Group on Substance Use Disorders: Practice Guideline for the Treatment of Patients With Substance Use Disorders, 2nd Edition. Washington, DC, American Psychiatric Association, 2010

World Health Organization: Global Status Report on Noncommunicable Diseases 2010: Description of the Global Burden of NCDs, Their Risk Factors and Determinants. April 2011a. Available at: http://www.who.int/nmh/publications/ncd_report2010/en/. Accessed July 25, 2013.

World Health Organization: Mental and behavioural disorders due to psychoactive substance use (F10-F19), in Chapter V: Mental and Behavioural Disorders (F00-F99) of International Statistical Classification of Diseases and Related Health Problems 10th Revision, 2010 Edition (ICD-10 Version:2010). Geneva, World Health Organization, 2011b. Available at: http://apps.who.int/classifications/icdl0/browse/2010/en#/F10-F19. Accessed July 25, 2013.

Wu L, Schlenger W, Galvin D: Concurrent use of methamphetamine, MDMA, LSD, ketamine, GHB, and flunitrazepam among American youths. Drug Alcohol Depend 84:102-113, 2006

Wu L-T, Parrott AC, Ringwalt CL, et al: The high prevalence of substance use disorders among recent MDMA users compared with other drug users: implications for intervention. Addict Behav 34:654-661, 2009a

Wu L-T, Parrott AC, Ringwalt CL, et al: The variety of ecstasy/MDMA users: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Am J Addict 18:452-461, 2009b

Yip SW, Doherty J, Wakeley J, et al: Reduced subjective response to acute ethanol administration among young men with a broad bipolar phenotype. Neuropsychopharmacology 37:1808-1815, 2012

Suggested Readings

Fiore M, Jaen C, Baker T, et al: A clinical practice guideline for treating tobacco use and dependence: 2008 update. A U.S. Public Health Service report. Am J Prev Med 35:158-176, 2008

Galanter M, Kleber HD (eds): The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition. Washington, DC, American Psychiatric Publishing, 2008

Goldstein RZ, Volkow ND: Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 12:652-669, 2011

Haile CN, Mahoney JJ 3rd, Newton TF, et al: Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: focus on dopamine, norepinephrine and glutamate. Pharmacol Ther 134:260-277, 2012

Kleber HD, Weiss RD, Anton RF Jr, et al: Practice Guidelines for the Treatment of Patients With Substance Use Disorders, 2nd Edition. Washington, DC, American Psychiatric Publishing, 2006

Kosten TR, Newton TF 2nd, De La Garza R 2nd, et al: Cocaine and Methamphet-amine Dependence: Advances in Treatment. Washington, DC, American Psychiatric Publishing, 2011

Ries R, Fiellin D, Miller M, et al (eds): Principles of Addiction Medicine, 4th Edition. Philadelphia, PA, Lippincott Williams & Wilkins, 2009

Volkow ND, Wang G-J, Fowler JS, et al: Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain's control circuit. Bioessays 32:748-755, 2010