9 – Substance Use Disorders




Abstract




Substance use disorders are highly prevalent, affecting millions of Americans directly (social, occupational, and health problems) and indirectly (billions of dollars in health care costs and lost revenues due to disability). This section briefly introduces the chemical classification and neurobehavioral properties of the most commonly misused substances.





9 Substance Use Disorders


Hilary S. Connery , Mark J. Albanese , Jeffrey J. DeVido , Kevin P. Hill , R. Kathryn McHugh , Dana Sarvey , Joji Suzuki , and Roger D. Weiss This chapter was created with the support of National Institute on Drug Abuse UG1DA15831 and K24DA022288 (RW) and DA035297 (RKM).



Overview of Substance Use Disorders



Classification of Commonly Misused Substances


Substance use disorders are highly prevalent, affecting millions of Americans directly (social, occupational, and health problems) and indirectly (billions of dollars in health care costs and lost revenues due to disability). This section briefly introduces the chemical classification and neurobehavioral properties of the most commonly misused substances.



Alcohol

Ethyl alcohol is the psychoactive ingredient in intoxicating beverages (beer, wine, and liquor) and fermented fruit. Alcohol has complex central neuromodulatory effects accounting for its psychoactive properties, including inhibition of NMDA-mediated glutamatergic excitatory neurotransmission and potentiation of inhibitory GABAA-mediated neurotransmission, as well as potentiation of glycine, 5-HT3 serotonergic, and nicotinic cholinergic signaling. It also potentiates ion channel activity via effects on L-type calcium ion channels and G-protein inwardly rectifying potassium (GIRK) ion channels. In low doses, drinking alcohol results in euphoria, relaxation, and lowered inhibitions. Higher doses can result in sedation, slurred speech, nausea, emotional lability, loss of coordination, visual disturbances, impaired memory, sexual dysfunction, loss of consciousness, increased risk for injury or violence, fetal damage (in pregnant women), depression, neurologic disturbances, hypertension, liver and heart disease, and fatal overdose. Problematic drinking may take the form of either (1) drinking heavily most or all days of the week or (2) binge-pattern drinking, in which drinking episodes have high volume consumption but low frequency of occurrence. The abrupt cessation of problematic daily drinking can lead to life-threatening withdrawal seizures, thus necessitating medically supervised detoxification.


Patients typically seek medical care only after developing a relatively severe alcohol use disorder. Therefore, screening individual alcohol consumption patterns is routinely advised to detect opportunities for early intervention and prevention of alcohol use disorders, such as providing normative feedback and encouraging goal-setting or behavioral counseling to reduce drinking. Patients with severe alcohol use disorders may also benefit from adjunct medications that reduce heavy drinking days and improve abstinence outcomes.



Opioids

Opioids refer both to natural derivatives of the opium poppy plant as well as to synthetic and semi-synthetic ligands that activate central mu-opioid receptors (e.g., heroin and narcotic analgesics) and induce euphoria, sedation, and at high concentrations, respiratory depression. Opioid use disorders have increased ten-fold in the past decade due to the prevalence of narcotic analgesic supplies (licit and illicit), the increased purity of heroin, and the rise of fentanyl, a highly potent synthetic opioid. According to the Centers for Disease Control and Prevention (CDC), 128 Americans die each day from opioid-related overdoses. Depending on the specific drug, opioids can be consumed by oral, sublingual, transdermal, and intranasal use; they may also be prepared to be smoked or injected subcutaneously or intravenously. Opioids may have additional health consequences including impaired coordination, dizziness, confusion, nausea, constipation, anorexia, and sexual dysfunction/hypogonadal syndrome. Injection drug use is associated with abscesses, cellulitis, endocarditis, hepatitis B and C, and HIV infection. Accidental overdose deaths have risen sharply with the increased prevalence of opioid use disorders but may be prevented by the timely administration of intravenous or intranasal naloxone. Although opioid withdrawal is very uncomfortable and marked by runny nose, muscle cramps, general aches, nausea/diarrhea, insomnia, opioid craving, and irritability, it is not typically life-threatening, allowing many patients presenting for treatment the option of outpatient detoxification. Medication maintenance therapies (opioid agonists or antagonists) that compete for central mu-opioid receptors are advised for severe opioid use disorders, as they roughly double a patient’s chances of sustaining opioid abstinence following detoxification.



Tobacco

Although cigarette smoking has declined in the United States in recent years, smoking remains the number one preventable cause of morbidity and mortality in the United States and globally. The addictive component of tobacco, nicotine, is found in cigarettes, cigars, “hookah,” electronic cigarettes, and smokeless tobacco products (chew, snuff). Short-term effects of tobacco use include increased blood pressure/heart rate and cognitive enhancement due to nicotine’s activation of nicotinergic cholinergic receptors in the brain. Long-term effects of tobacco use include chronic lung disease; cardiovascular disease; cancers of the mouth, pharynx, larynx, esophagus, stomach, pancreas, cervix, kidney, and bladder; acute myeloid leukemia; and fetal growth restriction in pregnancy. A nicotine withdrawal syndrome will occur in abstinent chronic tobacco users, marked by irritability, anxiety, nicotine craving, poor concentration, and headaches. The unpleasant nature of nicotine withdrawal often leads to relapse, and this, along with greater social tolerance of nicotine use disorders compared with other substance use disorders, renders smoking cessation very challenging – the average smoker makes five or more quit attempts prior to successful cessation. Medications to assist cessation (nicotine replacement and other medications acting at central nicotinic cholinergic receptors) are routinely recommended to improve the probability of a successful quit attempt.



Cannabinoids

More people use marijuana than any other illicit drug, and trends of marijuana use among youth are concerning – use is on the rise, and perceptions of marijuana’s harm are declining. Cannabinoids, which can be smoked or eaten, are derived from natural marijuana hemp plant parts, hydroponically engineered hemp plants, and synthetic compounds referred to variously as “K2,” “Spice,” and “Incense,” among other names. Despite attempts by the US Food and Drug Administration (FDA) to limit exposure to synthetic cannabinoids, they remain illicitly available on the Internet and at some convenience stores (marketed as environmental incense or potpourri), and are a popular alternative to hemp cannabis in part because synthetic cannabinoids are not detectable by routine urine drug screens. Cannabinoid substances bind to central endocannabinoid receptors (primarily CB1 receptors, which are widely distributed, and also microglia CB2 receptors) to induce short-term effects of euphoria, slowed reaction time, relaxation, altered sensory perception, impaired coordination and balance, increased heart rate, increased appetite, impaired learning and memory, anxiety, panic attacks, and psychosis. Cannabis withdrawal in daily or near-daily users is marked by irritability, anxiety, insomnia, craving, and poor concentration, but it does not require medical attention. In contrast, synthetic cannabinoid intoxication can be life-threatening due to adrenergic dysregulation and psychosis, and may require supportive medical interventions during intoxication. To date, no medications have been approved by the FDA to assist in the treatment of cannabis use disorders.



Stimulants

Stimulants are popular drugs of abuse due to their powerful euphoric and cognitive-enhancing effects associated with central dopamine release. Commonly abused stimulants include cocaine, methamphetamine, prescription amphetamines, and synthetic cathinones referred to as “bath salts.” Methamphetamine use has soared in rural communities in the United States in the last ten years, in part due to the wide availability of ingredients that can be readily used to synthesize the drug in makeshift “labs.” “Bath salts” are sold illicitly disguised as potpourri, plant food, and bath additives in convenience stores, and consist of dried plant matter that has been sprayed with adherent stimulant chemicals. Stimulants may be smoked or taken by oral, intranasal, and intravenous routes. Short-term effects of stimulants may include increased heart rate, blood pressure, temperature, and metabolism; euphoria; increased energy and alertness; reduced appetite; increased libido; tremors; irritability; anxiety; panic attacks; paranoia; violent behavior; psychosis; cardiovascular spasm resulting in myocardial infarction and hemorrhagic stroke; and seizure. Long-term effects of stimulant use may include weight loss, insomnia, malnutrition and poor dentition, and nasal perforation. Stimulant users typically engage in binge-pattern use with episodes lasting days due to stimulant-induced insomnia, followed by a withdrawal syndrome consisting of severe dysphoria, dehydration, somnolence, and stimulant craving. Stimulant use is frequently paired with heightened sexual activity and is associated with risky sexual behaviors and HIV transmission. At this time, medications with established efficacy to assist the treatment of stimulant use disorders are unavailable.



Hallucinogens

Hallucinogens are popular among youth and include lysergic acid diethylamide (LSD), mescaline, psilocybin, methylenedioxymethamphetamine (MDMA), also known as “ecstasy,” and dimethyltryptamine (DMT). They are predominantly serotonergic agonists, although some compounds such as MDMA also have stimulant properties via enhanced noradrenergic and dopaminergic neurotransmission. MDMA and DMT, especially, have been established as popular “club drugs.” Hallucinogens can be ingested, smoked, inhaled, injected, or absorbed through the tissues of the mouth. Short-term effects of hallucinogens may include hallucination, altered states of perception, and nausea. Both LSD and mescaline can cause increased temperature, heart rate, and blood pressure; loss of appetite, sweating, insomnia, numbness, dizziness, weakness, tremors, impulsivity, and mood lability. Psilocybin use can result in nervousness, paranoia, and panic attacks. MDMA use can cause increased tactile sensitivity, empathic feelings, lowered inhibition, anxiety, chills, sweating, insomnia, muscle cramping, depression, impaired memory, and hyperthermia. Much of the risk that comes with hallucinogen use involves self-neglect or risky behavior during intoxication. Lasting effects of repeated hallucinogen exposure may include persistent perceptual disturbance disorder and problems with memory. There are no medical treatments specific to hallucinogen use disorders.



Dissociative Drugs

Dissociative drugs are notable for producing the feeling of being separate from one’s body and surroundings; this is due to the activation of central sigma receptors (dextromethorphan [DXM] and salvia divinorum), NMDA receptor antagonism, and dopamine transporter antagonism (phencyclidine [PCP] and ketamine). These drugs can be chewed, ingested, smoked, inhaled, and injected. In addition to the sensation of dissociation, these drugs may cause impaired motor function, anxiety, nausea, tremors, numbness, and memory impairment. PCP and ketamine use may also produce analgesia, psychosis, aggression, violence, slurred speech, impaired coordination, hallucinations, respiratory depression, seizure, and death. Medical treatment is limited to supportive management of intoxication syndromes.



Anabolic-Androgenic Steroids

Anabolic-androgenic steroids are abused by professional and amateur athletes interested in boosting their athletic performance and/or appearance. Steroids may be ingested, injected, or applied to the skin. While the use of steroids does not produce euphoria, long-term effects of steroid use may include hypertension, left ventricular hypertrophy and cardiac dysfunction, changes in blood clotting and cholesterol, hostility and aggression, liver cysts, infertility, and acne. Steroid use in men may increase the risk of prostate cancer and may also lead to reduced sperm production, shrunken testicles, or breast enlargement. Steroid use in women (far less common) may lead to menstrual irregularities and increased masculine characteristics. Medical treatment is limited to the cessation of steroid use and supportive management of long-term sequelae.



Inhalants

Inhalants are popular among those looking for an easily accessible “high” and thus often used by adolescents and youth. Many household items, especially cleaning supplies, glues, gases, and paints may function as inhalants administered through the nose or mouth (“huffing”). While the effects of inhalants may vary by substance, they are all toxic chemical vapors with differing degrees of neurotoxicity. Short-term effects may include stimulation, loss of inhibition, headache, nausea, vomiting, slurred speech, or loss of coordination; long-term use may be associated with severe cognitive disorders, dementia, and death by suffocation. To date, there are no medical therapies to treat inhalant use disorders.



Sedative-Hypnotics

Sedative-hypnotics (benzodiazepines, barbiturates, and zolpidem-like drugs) potentiate central inhibitory γ-aminobutyric acid (GABA) neurotransmission by neuromodulatory binding to GABAA receptor subunits. They are typically ingested or injected and used for their anxiolytic and relaxation effects, or to augment other drug use (such as opioid use). Short-term use of sedative-hypnotics may cause sedation, muscle relaxation, confusion, memory impairment, dizziness, and impaired coordination. Chronic sedative-hypnotic misuse may be associated with impaired memory and impaired motor coordination. As with alcohol, abrupt cessation of daily sedative-hypnotic use can result in life-threatening withdrawal seizures. Thus medically supervised detoxification is recommended. Severe sedative-hypnotic use disorders are generally treated by gradual tapering of the misused drug under outpatient physician monitoring.



Epidemiology and Impact of Substance Use Disorders


In the early 1980s, the pioneering Epidemiologic Catchment Area (ECA) study provided the first systematic national assessment of the prevalence of substance use disorders in the United States. Subsequent to the ECA, several other studies have helped refine and track regional and national trends in substance use. These surveys consistently show that substance use disorders are (1) highly prevalent among all ages, beginning in late adolescence, and both genders; (2) frequently co-occur with significant medical and psychiatric illnesses; (3) are associated with high costs at both individual and societal levels; and (4) continue to be largely underdetected and undertreated, in part due to persistent cultural stigma and barriers to medical care, and in part due to the individual’s minimization of symptoms deriving from substance abuse.


The World Health Organization (WHO) estimates that 5.4 percent of the total global disease burden results from alcohol and/or illicit drug use, and the mortality rate is highest for substance use disorder among all other mental health disorders. According to the 2016 National Survey on Drug Use and Health (NSDUH), 28.6 million Americans ages 12 and older reported past-month use of illicit drug(s), representing 10 percent of the population. Just over half of Americans in this age group (136.7 million) reported past-month alcohol use, with 48 percent of these reporting binge drinking (5 or more drinks within a few hours for men and 4 or more for women). An estimated 20.1 million Americans met DSM-IV criteria for a past-year substance use disorder (DSM-IV abuse + dependence, which should capture all in the substance use disorder category identified in DSM-5 updated criteria), with 2.3 million of these individuals having both alcohol and illicit drug(s) use disorders. Alcohol use disorder is twice as common as drug use disorder, with 15.1 million versus 7.4 million affected, respectively. Marijuana is the most commonly used drug among all age groups, with 24 million past-month users, of which 4 million met the criteria for past-year marijuana use disorder (1.5 percent of Americans). Prescription opioid use disorder was 2–3 times more commonly reported (1.8 million affected) than cocaine (900,000), methamphetamine (700,000), heroin (600,000), and prescription stimulant (500,000) use disorders. A total of 63.4 million Americans use a tobacco product, the majority (51.3 million) being cigarette smokers, making tobacco-related illnesses the most common preventable causes of morbidity, mortality, and societal health costs (estimated at $300 billion annually in the United States).


Substance use disorders frequently co-occur with other mental illnesses, and having any mental illness doubles an individual’s lifetime risk for illicit drug use and/or having a substance use disorder. One in four suicides is associated with having an alcohol use disorder, and most accidental overdose deaths in the United States in 2016 were associated with opioids.


The World Health Organization reports that up to half of all tobacco users will die from tobacco-related causes, with 6 million deaths due to direct use of tobacco and another 890,000 deaths due to second-hand smoke exposures. Second to tobacco use is alcohol use, with 5.9 percent of all deaths worldwide associated with alcohol-induced injuries and accidents, cancers, cardiovascular diseases, and liver cirrhosis. Among illicit drug users, injection drug use is most closely associated with sexually transmitted disease and life-threatening blood-borne infections associated with needle sharing, such as HIV, HBV, and HCV. Illicit drug use is also closely linked to tuberculosis infection and malnutrition. In addition to disease burden, the socioeconomic impact of substance use disorders includes diminished academic achievement, lower vocational level, and greater on-the-job injuries, as well as increased violence, domestic abuse and neglect, and incarceration for drug-related crimes.


Public prevention efforts include raising the perception of risk associated with substance use, diminishing easy access to substances as defined by legal age limits, policies limiting the geographic density of sales, higher sales taxes imposed on drugs of abuse, and recent mandates to support smoke-free public environments. Other prevention efforts specifically target vulnerable populations, such as campus security enforcement directed toward underage drinking and illicit drug use, mandated substance screening on parole and drug court-mandated treatment for individuals whose crimes are largely substance-related, safer opioid treatment interventions for those with co-occurring pain disorders, and culturally sensitive interventions for at-risk populations (e.g., American Indians, native Alaskans, LGBTQ, and chronically homeless individuals).



Etiology of Substance Use Disorders


Substance use disorders, like many other illnesses, have a variety of determinants, including genetic and psychological vulnerability, the nature of the drug and its effect on a specific individual, cultural mores, the availability and legality (or lack thereof) of a particular substance, and the context in which an individual takes a drug (e.g., morphine administered after major surgery versus oxycodone taken at a party). Given the complexity of the etiology of substance abuse and substance use disorders, one way to increase our understanding of this phenomenon is to invoke the classic public health perspective typically used in the context of infectious disease: that the development of a substance use disorder, like an infectious disease, involves an interaction between (1) host, (2) agent (in this case, a specific substance), and (3) environment. The following sections review how each of these three factors may influence the probability that an individual will engage in substance abuse or develop a substance use disorder.



The Host

Both biological and psychological characteristics of an individual will influence the probability of substance abuse or expressing a substance use disorder. For example, having a family history of alcohol use disorder substantially increases the lifetime probability of expressing an alcohol use disorder, and this is due to multiple factors. Studies show that having a parent with severe alcohol use disorder roughly quadruples the risk for alcohol use disorder, and having a sibling with alcohol use disorder is also predictive of increased risk. Yet the fact that alcohol use disorder runs in families does not tell us whether this occurs as the result of genetic or environmental influences, or both; we know that both hemophilia and speaking English runs in families, for example, but the former is genetically transmitted and the latter is an environmentally acquired behavior.


To determine mediators, twin studies have been informative in that monozygotic (identical) twins show a higher concordance rate for severe alcohol use disorders than dizygotic (non-identical) twin pairs, suggesting an etiologic role of genetic heritability. It could be argued, however, that monozygotic and dizygotic twins have differing environmental experiences (i.e., they may be treated differently); therefore these data alone cannot fully inform etiology. Adoption studies help discern genetic from environmental influences, as these studies examine individuals who are adopted soon after birth and thus carry a potential genetic risk for alcohol use disorder from biological parents who do not raise them and an environmental risk from adoptive parents with no biological relationship. Interestingly, studies of this type generally demonstrate that biological children of parents with severe alcohol use disorder retain a greater lifetime risk of expressing alcohol use disorder, regardless of environmental upbringing, confirming the heritability of alcohol use disorder.


What is it about this complex neurobehavioral disorder that could be inherited? Differential neurobiological sensitivity to alcohol exposure appears to be one heritable factor that confers either risk or protection. A series of seminal studies conducted by Schuckit and colleagues compared alcohol responses in young, healthy men with a family history of severe alcohol use disorder to an age-matched group of men without this family history. The two groups had significant differences in both subjective and objective response to alcohol: those with a positive family history had attenuated responses to alcohol at equivalent blood alcohol levels, compared with those with a negative family history. Those at-risk appear to have a higher tolerance to the effects of alcohol, which would be predicted to lead to increased alcohol consumption in order to achieve feedback that one is intoxicated. Considering this, intoxication perception serves as a satiety feedback signal (i.e., “I have now had enough to drink.”). Malfunction of this feedback loop would cause an individual to perceive intoxication only after blood alcohol levels are well beyond low-risk levels; health consequences along with social/occupational consequences will more likely occur, and impaired executive functioning during intoxication will facilitate perseverative consumption, leading over time to increased tolerance and physiologic dependence.


Subsequent studies have examined potential genetic factors contributing to the differential response to alcohol. One area of intense interest has been the metabolic pathway for alcohol, specifically the enzymes alcohol dehydrogenase and aldehyde dehydrogenase. Since aldehyde dehydrogenase is responsible for the oxidation of acetaldehyde, deficiencies in this enzyme cause an accumulation of acetaldehyde with alcohol ingestion, which can lead to aversive symptoms such as flushing, headache, and tachycardia (not unlike the mechanism of action of the medication disulfiram, as discussed later in the section “Disulfiram in the Treatment of Alcohol Use Disorders”). A substantial minority of the Asian population has reduced aldehyde dehydrogenase activity, resulting in aversive conditioned response to alcohol consumption and thus avoidance of drinking. This genetic variant would be protective against developing alcohol use disorder.


Other biological factors that appear to influence the treatment of alcohol use disorder involve the mu-opioid receptor system. Genetic variance in the mu-opioid receptor OPRM1 gene affects the response to the opioid antagonist, naltrexone, an evidence-based medication used to treat severe alcohol use disorders. Patients in whom aspartic acid (Asp) replaces asparagine (Asn) at position 40 of the mu-opioid receptor are more likely to respond beneficially to naltrexone than those who are homozygous for the Asn40 allele.



The Agent

The principle of reinforcement plays an important role in the development of substance use disorders. Common drugs of abuse are all highly reinforcing, meaning that subjectively perceived reward facilitates and trains repeated drug-taking behaviors. Solid evidence supporting the reinforcing properties of substances of abuse is derived from both animal and human self-administration research. In the classic laboratory paradigm, an animal is trained to “work” for a substance by performing a particular behavior (e.g., pressing a lever) that results in the administration of a drug. The animal may then be required to increase the frequency of that behavior to obtain the drug again; the strength of the reinforcing property of that drug can be measured as a function of the number of times an animal is willing to press the lever to obtain the drug (how hard the animal will “work” for reward). Reinforcement can also be examined in studies in which the animal presses one lever to receive a drug and a different lever to receive food, a natural reinforcer; comparative strength of the two reinforcing stimuli can thus be measured. An extreme example of drug reinforcement is that rhesus monkeys given free access to intravenous cocaine will self-administer the drug until it results in death. In this case, the supernatural strength of the stimulant reward essentially “hijacks” all natural survival behaviors, including rest and seeking nourishment.


Although the common drugs of abuse vary in their effects, the method by which they exert their reinforcing effects share some similarities. Specifically, many substances of abuse exert their reinforcing properties by amplifying dopamine neurotransmission or direct release within areas of the mesolimbic dopaminergic pathways, particularly the nucleus accumbens and amygdala. Other neurotransmitters implicated in reward/reinforcement include glutamate, endorphins and enkephalins (endogenous opioids), norepinephrine, and serotonin.



The Environment

Substance use and misuse occur within a context of familial, regional, and national culture, social attitudes and mores, laws, religious beliefs and practices, and varying accessibility. All of these factors influence the regional prevalence of substance use and misuse, and some of these factors, particularly accessibility, will influence the probability of a higher frequency of substance use, a risk factor for developing a substance use disorder. For instance, the two substances with the highest rates of physiologic dependence and substance use disorder in the United States are alcohol and nicotine, largely due to high accessibility by virtue of being legally available to adults. Additionally, the competitive market within legal sales drives down cost, another factor increasing accessibility to the average individual. It has been repeatedly demonstrated in studies throughout the world that increasing cost of substances effects use: restricting the accessibility of alcohol and cigarettes through increased taxes leads to reduced consumption, while increasing accessibility by extending the hours during which one may purchase alcohol and cigarettes leads to increased sales and higher consumption.


Perceptions of substance use risk also substantially influence substance use prevalence and initiation of substance use. For example, in the mid-1980s, public perceptions of cocaine shifted from that of a relatively harmless “party drug” to a potentially dangerous drug that could lead to overdose and death; the number of people who used cocaine during that time declined accordingly. In 2012, cannabis use among adolescents and young adults increased with reduced perceptions of cannabis risk among these cohorts. The decreased perception of risk is occurring within the cultural context of the medical marijuana and recreational legalization movement; here, a cultural influence (medical marijuana and legalization promotion) both increases access directly to the consumer (especially in states with approved recreational legalization and/or broad indications for being recommended medical marijuana) and indirectly via lowered perceptions of harm with use (in this case, also with increased perceptions of safety and benefit with use).


The context in which a drug is taken also influences the natural history of its use. At no time was this more clearly demonstrated than when large numbers of members of the United States military used heroin while fighting in the Vietnam War. There was substantial concern that when these troops returned to the United States, there would be a dramatic increase in the rate of heroin addiction in this country; however, that did not occur. Interestingly, only a small percentage of those who used heroin while in Vietnam continued to do so after returning to the United States. The role of context was critical here. In Vietnam, heroin was easily available, highly pure, and inexpensive. Moreover, for US troops the setting was uniquely stressful. Upon their return to the United States, many military personnel would have encountered access barriers, including challenges of obtaining an illicit drug, lower purity (i.e., lower quality of reinforcement) and higher cost, cultural disapproval, as well as competing factors against drug-taking, such as access to college or work-study programs through veterans benefits. Additionally, the home environment was completely different, such that cue-conditioned and stress-conditioned drug-taking associated with the Vietnam combat theater would be substantially diminished.


The role of context is important in the transition from substance use to substance use disorders in another way, namely through classical (Pavlovian) conditioning. When people use reinforcing substances within a particular environment (e.g., a neighborhood), they are likely to experience a strong desire or craving to use that substance again upon re-entry to that environment. Indeed, this type of conditioned response that triggers substance craving remains for a substantial time after cessation of substance use (i.e., it extinguishes slowly). Other conditioned cues associated with substance use (e.g., hearing someone open a can or bottle of beer, smelling cigarette smoke, seeing a hypodermic needle) may provoke thoughts and cravings to use that substance, or even another substance of abuse. Over time, these conditioned associations will weaken, but they endure in learned memory, and thereby constitute an enduring risk factor for relapse to substance use.


In sum, the development of substance use disorders represents a complex interplay between individual biological vulnerability, the reinforcing properties of a substance taken, the frequency and quantity of a substance taken repeatedly, the ease of access to the substance, and sociocultural and environmental context. The complexity of these interactions helps to explain the heterogeneity of substance use disorders observed in community populations.



Clinical Features and Course



Core Clinical Features

Problematic substance use can range from discrete episodes of hazardous or harmful use to a pattern of substance use meeting diagnostic criteria for substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). A universal clinical feature of all problematic substance use is either the occurrence or a credible threat of an unintended negative consequence directly caused by or related to substance use. Examples of this would include any of the following occurring in the context of substance use: operating machinery or a motor vehicle while intoxicated, risky sexual behavior, uncharacteristic interpersonal altercation or fight, absenteeism from work or school, physical injury (such as a fall or hypothermia), and acute medical or psychiatric illness exacerbation caused by substance use. Substance use also significantly increases the risk for both suicide and violent behavior, including homicide, as well as increasing the risk of becoming the victim of a violent act.


Core features of a substance use disorder are defined by maladaptive patterns of substance use (episodic or daily) associated with predictable biological, cognitive, and behavioral changes. These changes manifest as (1) the development of tolerance (increased self-dosing in order to achieve a desired effect) or a characteristic withdrawal syndrome in the absence of the substance, (2) anticipation and craving for the substance and preoccupation with obtaining the substance, (3) loss of self-regulation over substance use (using greater amount or more frequently than intended), and (4) increased time spent in obtaining, using, or recovering from substance use, at the cost of time spent engaged in healthy behaviors and interests. It is worth emphasizing that individuals can meet criteria for having a substance use disorder without developing physiologic tolerance or withdrawal. Typically, individuals having a substance use disorder can recognize negative consequences related to their patterns of substance use, yet substance use persists because of more powerful neurobiological incentives to use substances, either for pleasure/reward or to experience relief from stress or withdrawal syndromes. These natural incentives frequently override judgment or otherwise interferes with efforts to stop using substances, particularly when access to substances is readily available.


It is important to note that substance use disorders occur along a continuum of severity; it is thus possible to have a mild, moderate, or severe substance use disorder. Moreover, some but not all substance use disorders progress; some individuals have mild problems for many years without developing more serious consequences.



Acute Intoxication

Individuals acutely under the influence of a substance display recognizable clinical signs and symptoms of substance intoxication evident on mental status exam and physical exam. Acute intoxication states are specific to the substance being used (as noted previously) and are described in terms of neurological depressant, stimulant, or hallucinogenic effects. Polysubstance use produces mixed effects; severe medical sequelae (e.g., cardiac arrhythmia, seizure, autonomic instability, respiratory depression) are seen with polysubstance use, high-dose or intravenous substance use, and substance use in medically compromised individuals.



Abstinence Syndromes

Abstinence syndromes are characteristic of individuals with physiological dependence as part of a substance use disorder. With repeated substance use, the brain will compensate for abnormal neurochemical signaling induced by substance exposure via adjustments in inhibitory and excitatory neurotransmission (primarily gamma-aminobutyric acid (GABA) and glutamate, respectively), a process referred to as allostasis. Abrupt cessation of substance use results in physiological and psychological signs and symptoms reflecting allostatic changes in neural signaling, with recognizable “rebound” syndromes that typically oppose the acute effects of the substance (e.g., hyperexcitability with CNS depressant use and fatigue with CNS stimulant use).



Physical Examination and Biomarkers

Physical examination is helpful not only in detecting acute intoxication and abstinence syndromes associated with substance use but also in detecting chronic health effects and/or social harm related to substance use. The following sections describe substance-specific signs and symptoms and laboratory tests that can assist diagnosis and direct treatment interventions.



Alcohol Use

Heavy drinking is defined as having at least four (women) or five (men) drinks per drinking episode and is correlated with increased medical consequences and risk for several cancers. Alcohol is neurotoxic, and overuse may lead to peripheral neuropathies, cerebellar degeneration with gait instability and abnormal reflexes, loss of cerebral gray matter and cognitive decline, and in pregnant women, fetal alcohol spectrum disorders. Chronic heavy alcohol use may be associated with high blood pressure, thiamine deficiency and poor nutrition, gastrointestinal bleeding and gastroesophageal reflux, pancreatitis, fatty liver and hepatic cirrhosis, cardiomyopathy, and stigmata of the skin including flushing and spider angiomas. Abnormalities in complete blood count (enlarged mean corpuscular volume and decreased hematocrit), hepatic panel (elevated AST, ALT, GGT, and CDT), elevated serum amylase, and decreased serum magnesium may be seen in individuals with more advanced alcohol use disorders. A smell of alcohol on the breath may be confirmed with a calibrated breathalyzer to determine blood alcohol levels, conferring risk for impaired driving, alcohol poisoning, or alcohol withdrawal syndrome.



Tobacco Use

Cigarette smoking and the use of smokeless tobacco products are significantly associated with increased cancer risk of multiple types, especially of the lung and oropharynx, due to “tar” contaminants that are carcinogenic, particularly upon combustion with cigarette smoking. Smoking is associated with respiratory compromise (asthma, emphysema, chronic obstructive pulmonary disease) and significantly increases an individual’s risk for coronary artery disease, high blood pressure, cerebrovascular accidents, blood clotting, peripheral vascular compromise, and poor wound healing. Second-hand smoke exposure is associated with increased risk for lung cancer, respiratory compromise, and cardiovascular disease in adults; in children, passive exposure to second-hand smoke is associated with respiratory compromise (especially asthma), increased incidence of respiratory viral illness and ear infections, and sudden infant death syndrome. Tarry yellowing of fingers, smoke on breath, abnormalities on pulmonary auscultation and pulmonary function testing, and subjective symptoms of shortness of breath are common indicators of nicotine dependence and tobacco use. Pregnant women who smoke are at greater risk for miscarriage, intrauterine growth restriction, and premature labor.



Cannabis Use

Like cigarette smoking, chronic heavy use of smoked marijuana is associated with increased risk for respiratory illnesses, cancer, and heart attack. Daily or near-daily cannabis use has been associated with negative effects on learning, memory, mood, and capacity to engage in normal pleasurable activities. Heavy use of cannabis in adolescence has been associated with an increased risk for having a lifetime psychotic episode. The neuropsychiatric risks of cannabis use are greatest for heavy daily smokers, those who begin smoking in early adolescence, and babies exposed to intrauterine cannabis due to mother’s use during pregnancy. A pungent cannabis odor and glassy, injected sclerae on physical exam are signs of acute cannabis intoxication, which more than doubles the risk of having a motor vehicle accident. Urine toxicology in daily users may remain positive for cannabinoids for up to thirty days.



Opioid Use

Accidental overdose fatalities due to respiratory depression with illicit and prescribed opioid use quadrupled in the last decade, in parallel with national increases in prescription opioid prescribing. Prescription opioid use is associated with the majority (62 percent) of reported overdoses compared with heroin use alone; more recently, illicitly manufactured fentanyl analogs contribute to rising rates of opioid overdose deaths. On physical exam, drowsiness and pupillary constriction with depressed vital signs (decreased pulse, respiratory rate, and blood pressure) are suggestive of acute use, while the appearance of “track marks” (erythema at injection sites) and/or a history of opioid withdrawal symptoms and doctor-shopping or “lost” prescriptions suggest a more chronic opioid use disorder. Babies with intrauterine opioid exposure are at risk for low birth weight and neurodevelopmental abnormalities, and may require medical treatment for opioid abstinence syndrome upon birth. Urine toxicology will detect codeine and morphine metabolites of heroin within one to three days of use, but routine panels will not identify many prescription opioids; clinical suspicion warrants a specially ordered narcotic panel.



Cocaine/Stimulant Use

Cocaine, methamphetamine, and prescription stimulant (e.g., amphetamine, dexedrine, methylphenidate) use may be oral, intranasal, smoked (crack cocaine), or intravenous and is associated with significant increases in risk for elevated heart rate, temperature and blood pressure, cardiac arrhythmias, abdominal pain and vomiting, stroke, seizure, aggressive behavior, hallucinations/paranoid ideation, and sudden death. Increasing access to higher-purity methamphetamine has significantly contributed to increasing drug overdose death rates. Stimulant use during pregnancy significantly increases the fetal risk of abruptio placentae, low birth weight, and neurodevelopmental abnormalities. Chronic use is associated with gingivitis and tooth decay, sinus infection and perforated nasal septum, and depressed mood with increased risk for suicide. Intravenous use increases the risk of blood-borne infections. Concurrent cocaine and alcohol use produces the hepatic metabolite, cocaethylene, which increases the risk of sudden cardiac death, seizure, and hemorrhagic stroke.


Urine toxicology detects use within one to three days. Since many stimulant users have an episodic binge pattern of use, hair sampling toxicology may be more useful for detecting less frequent episodes during the previous ninety days.



Hallucinogens and Synthetic Drug Use

A variety of dangerous synthetic drugs, primarily used by teenagers and young adults, are commonly referred to as “club drugs” due to the proclivity to use these drugs within social gatherings. This category includes many drugs – for example, stimulants such as methamphetamine, MDMA (“ecstasy”), and synthetic cathinones (“bath salts”); hallucinogens and dissociative drugs such as LSD, GHB, ketamine, salvia, and synthetic cannabinoids such as “K-2” and “spice” – with potent hallucinogen effects and varying physiological effects including vomiting, insomnia, temperature dysregulation and dehydration, autonomic instability, psychosis, delirium, and sudden death. In the past decade, a sharp rise in the accessibility of new synthetic compounds has posed problems to clinical detection, as many compounds are not detectable with routinely available toxicology panels, and clinical presentation is variable and often confounded by polysubstance use. Seeking data from collateral sources (friends and family) is imperative if clinical suspicion is high and toxicology is unrevealing.



Heterogeneous Course of Illness

Substance use disorders range in both severity and chronicity and the majority of individuals with problematic substance use or substance use disorder never receive medical treatment. For example, a large national epidemiologic database revealed five distinct subtypes of DSM-IV alcohol dependence, with a majority of individuals experiencing natural remission and a small fraction progressing to persistent disease. Diagnosis of the individual phenotype is critical to developing appropriate-level treatment interventions.



Epigenetic Factors

Substance use disorders are heritable, multifactorial disorders, defined as the result of multiple genes interacting with environmental and lifestyle factors. As such, the phenotype spectrum is broad, and within any individual, the frequency of substance exposures determines neuroadaptive molecular and cellular changes that may result in stable alterations of gene expression, termed epigenetic mechanisms of functional plasticity. The good news here is that no matter how vulnerable a person’s genetic predisposition to substance use disorders, disease is not expressed if substance exposure is prevented.



Individual Protective Factors

Many factors have been identified in youth and adults that protect against the initiation of substance use and/or support efforts to stop using substances. These include older age at first use, lack of immediate access to substances in social networks and environment, higher educational achievement, close family supports, after-school monitoring and structure, being employed, and having cultural and spiritual values and beliefs that promote abstinence from substance use or use in moderation, whereby drinking is viewed as acceptable but getting drunk is not.



Individual Risk Factors

Risk factors for problematic substance use are both biological and environmental. Biological risk factors include a family history of substance use disorders and psychiatric disorders, having a chronic pain disorder or psychiatric disorder, and temperamental factors such as impulsivity and aggressiveness. Other risk factors include young age of first use, easy access to substances in social networks and environment, any history of childhood trauma, lack of social supports and structured activity, poverty, and acute negative life events or loss such as the death of a spouse or sudden loss of employment.



Clinical Evaluation and Differential Diagnosis of Substance Use Disorders


According to the 2016 National Survey on Drug Use and Health, the vast majority (89 percent) of Americans with a substance use disorder report no treatment in the past year. Having an untreated substance use disorder increases the likelihood of developing other illnesses or failing to respond adequately to treatment aimed at other illnesses. Thus it is recommended that every clinician screen for problematic substance use at every clinical encounter. It is also helpful for clinicians to be trained in interviewing styles, such as motivational interviewing, that are designed to elicit self-report data on sensitive topics for which collaborative behavioral change goals may be advisable, and to support patient-clinician collaboration.



Acute Syndromes: Intoxication, Impairment, and Injury

Substance intoxication is often suspected in a patient who presents to a clinical setting with an altered mental status. The patient may appear confused, “high,” drowsy, irritable, euphoric, anxious, paranoid, disoriented, and so forth. In such situations, clinicians screen for substance use as a contributing factor by:




  • Asking about recent use of substances, both licit and illicit, in a non-judgmental and empathic manner



  • Looking for signs and symptoms expected with substance use during the physical examination



  • Performing toxicological analysis for suspected substances of abuse



  • Performing other laboratory or imaging studies to confirm or rule out a substance-related condition



  • When necessary or appropriate, asking significant others about the possibility of substance use


Patients may be reluctant to fully disclose substance use to clinicians due to stigma about substance use, fear of being negatively evaluated or treated, having previous negative experiences with health care, or concerns about confidentiality and/or liability. With this in mind, a patient’s denial of substance use is insufficient to rule out substance use contributing to altered mental status. Similarly, a patient’s self-report endorsing substance use may be incomplete in the type of substance or quantity/frequency of substance consumed. Patients may knowingly omit a history of illicit drug use while endorsing alcohol use, or they may intend to disclose fully but be unaware of having consumed adulterant drugs (e.g., cannabis adulterated with stimulants). Finally, patients frequently use multiple substances concurrently (e.g., heroin and cocaine, known as “speedballing”) or sequentially (e.g., drinking heavily and then using stimulants to remain awake), making the differential diagnosis challenging at times.


The consumption of alcoholic beverages, non-ethanol alcohols (e.g., antifreeze, rubbing alcohol, methanol fuel), as well as non-beverage ethanol (e.g., hand sanitizers, mouthwash) all produce similar signs and symptoms of intoxication. These signs and symptoms are overlapping with those seen with the use of sedatives and hypnotics (benzodiazepines, barbiturates, “z-drugs” such as zolpidem, and gamma-hydroxy-butyrate). Typically, a patient exhibits dose-dependent changes in mood and affect (initially social disinhibition, followed by dysphoric presentations upon larger volume consumption and increased blood alcohol levels), slurred speech, motor incoordination, flushed faces, disinhibited and/or perseverative behavior, red conjunctivae, and odors of alcohol that may be detectable on breath and perspiration. Ingesting toxic amounts (“alcohol poisoning”) leads to acute confusion, stupor, unconsciousness, and respiratory depression, especially if alcohol is combined with sedatives. A serum alcohol level or a breathalyzer should be obtained to determine the blood alcohol content (BAC). A patient who appears acutely intoxicated from alcohol but with a negative BAC should prompt serum analysis for isopropyl alcohol (rubbing alcohol), methanol, and ethylene glycol (antifreeze). Methanol ingestion is important to identify in a patient presenting with intoxication and acute visual changes, as permanent loss of vision may occur without emergency management of acute metabolic acidosis.


Although positive toxicology does not establish causality about altered mental status, a positive drug screen for benzodiazepines or other sedatives in an acutely intoxicated individual is important data informing risk for respiratory depression (especially with longer-acting sedatives) as well as the risk of future withdrawal seizure (especially with shorter-acting sedatives). It is important to note that routine urine toxicology may not reliably identify commonly misused sedatives (e.g., clonazepam is frequently not detected).


Acute opioid intoxication is important to recognize since respiratory depression with overdose may be rapidly reversed with the opioid antagonist, naloxone. In addition to experiencing analgesia, patients will present with dose-dependent changes in mood (relaxation to euphoria), level of consciousness (mild sedation to “nodding off” to unresponsive), constricted pupils, hypoventilation, and reduced gut motility. Additionally, patients may experience bradycardia, nausea, vomiting, hypothermia, and itching. “Nodding off” is a characteristic finding in opioid intoxication – the patient appears asleep but may be subjectively aware of the surroundings, is able to respond when spoken to, but is self-absorbed with the feelings of euphoria and relaxation. Obtaining a toxicology test for opioids is important, although caution is needed in the interpretation. Standard immunoassays are calibrated for detecting morphine and codeine (two metabolites of heroin), and other brief opioid panels may be calibrated to detect methadone, but routine assays may not detect opioid analgesics commonly associated with opioid use disorders (hydrocodone, oxycodone, fentanyl, and tramadol). Special order narcotic panels are recommended for suspected opioid misuse and overdose.


In contrast, acute stimulant (e.g., cocaine, methamphetamine, bath salts) intoxication induces dose-dependent cognitive enhancement, euphoria, psychomotor agitation, restlessness, hypersexuality, teeth grinding, and other sympathomimetic signs, such as tachycardia, hypertension, dilated pupils, and sweating. At very high doses, paranoia, hallucinations, delusions, seizure, and hyperthermia may be observed. Smokers of crack cocaine may present with acute injury to their lungs, complaining of fever, hemoptysis, shortness of breath, and cough (“crack lung”). Routine urine toxicology is generally sensitive for detecting the cocaine metabolite, benzoylecgonine. In contrast, urine testing for amphetamines is less reliable due to a large number of compounds that cross-react, resulting in high rates of false-positive results.


Intoxication from dissociative drugs (e.g., phencyclidine, ketamine, dextromethorphan) can produce signs and symptoms similar to alcohol and sedative intoxication – alterations in mood (i.e. euphoria, irritability, anxiety), ataxia, nystagmus, slurred speech, red conjunctivae, and motor incoordination. They can also produce sympathomimetic signs similar to those produced by cocaine and other stimulants – tachycardia, hypertension, flushing, and sweating. However, at higher doses, hypotension and bradycardia may be noted, as well as motor disturbances such as dystonia, tremors, seizures, and coma. Other notable changes include a sense of derealization or detachment from the world, numbness in extremities, agitation, hallucinations, paranoia, disorganized thought process, and violence toward the self or others. Persistent psychosis warrants testing for these substances.


Hallucinogens (e.g., LSD, psilocybin, mescaline) may produce an intoxication characterized by profound alterations in mood, perceptions, thought process, and behavior. Moods may vary tremendously from calm to agitated. Hallucinogen intoxication is heavily influenced by the psychological (“set”) and physical (“setting”) environment of the user. Therefore, a depressed patient taking LSD in an unsafe environment may experience a worsening of depression and anxiety. When dysphoria, paranoia, or anxiety is significant, the intoxication may lead to a “bad trip,” characterized by panic attacks. Autonomic changes are often noted, especially dilated pupils, tachycardia, and hyperthermia, sweating, and tremors. Routine toxicology will not detect these substances.


Polysubstance use is a lead cause of accidental fatalities presenting to emergency care and trauma units. Differential diagnosis of emergency presentations of accident or violent injury includes screening for substance abuse, which may be associated with such presentations in all age cohorts.

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Jul 27, 2021 | Posted by in PSYCHIATRY | Comments Off on 9 – Substance Use Disorders

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