Substance-Related Disorders I: Overview and Depressants, Stimulants, and Hallucinogens

Paul L. Doering and Robin Moorman Li

The book of Ecclesiastes wisely reminds us that “[W]hat has been will be again, what has been done will be done again; there is nothing new under the sun.”¹ It is doubtful that the author of these sage words was referring to the repeating cycle of substance abuse, but when it comes to this subject there rarely is anything new under the sun, and this metaphor aptly applies.

Psychoactive drug use dates back to prehistoric times and the Neolithic era (8500 to 4000 BC) where the earliest human use of psychoactive substances consisted almost exclusively of plants and fruits whose mood-altering qualities were accidentally discovered but subsequently deliberately grown.²

Ancient civilizations (4000 BC to BC 400) such as the Sumerians, Egyptians, Indians, Chinese, and South Americans used opium, alcohol, cannabis, peyote, psychedelic mushrooms, and coca leaves. The Middle Ages (400 to 1400) saw the use of psychoactive plants such as belladonna and psilocybin mushroom, used by witches and shamans for healing and spiritual purposes, and distilled alcohol and coffee, tea, and opium spread along the trade routes.²

Almost 5,000 years ago at the Temple of Imhotep, a center for treating mental illness, opium was used in an attempt to cure the mentally ill by inducing vision, performing rituals, and praying to the gods.² Hippocrates, the father of medicine, recommended opium as a painkiller and as a treatment of female hysteria.² Evidence of the inhalation of cannabis smoke can be found in the 3rd millennium BC, as indicated by charred cannabis seeds found in a ritual fire at an ancient burial site in present-day Romania.³ In 2003, a leather basket filled with cannabis leaf fragments and seeds was found next to a 2,500- to 2,800-year-old mummified shaman in the northwestern Xinjiang Uygur Autonomous Region of China.⁴ Thousands of years later, nearly every one of these drugs is still used today in one form or another for their mind-altering effects.

For any textbook to remain relevant, it must give emphasis to current information in any given content area. This means that space previously budgeted to one subject must give way to more recent trends. For example, if this chapter was written in the late 1960s, great attention would be given to the use and abuse of lysergic acid diethylamide (LSD) or methamphetamine.^5,6 If it was written in the late 1970s, the epidemic abuse of hydromorphone (Dilaudid) would be featured.⁷

In the mid- to late 1970s great attention would be given to the abuse of methaqualone (Quaalude).⁸ Somewhere along the way, the abuse of pentazocine would take center stage.⁹ Amphetamine abuse has come, gone, and come back again.¹⁰ γ-Hydroxybutyric acid (GHB) made a sudden and dramatic appearance on the scene, but its use has lessened in the past years.¹¹ The current epidemic of prescription drug abuse has skyrocketed its way into prominence. Hallucinogens such as dimethyltryptamine (DMT) and phenylethylamine derivatives are making a strong comeback.

By no means does this suggest that these above-mentioned drugs have disappeared, but instead many have taken a back seat to other, more commonly encountered drugs. For this reason, this rewrite of the present chapter and the one to follow will leave out some of the information from previous editions. The interested reader should consult prior editions of this textbook for information about these substances.

The lack of a common vocabulary in substance abuse treatment and prevention leads to several problems. Wide arrays of terms are in common use, many without precise meaning. This lack of universal agreement on language hampers effective communication among professionals and leads to difficulties in formulating public policy and administering third-party reimbursement programs.

In 2003, the Liaison Committee on Pain and Addiction, a collaborative effort of the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine, developed definitions related to the use of medications for the treatment of pain consistent with current understanding of relevant neurobiology, pharmacology, and appropriate clinical practice. The definitions have been approved by each of the three collaborating organizations. The following definitions resulted from this consensus development committee¹²:

      1. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following five C’s: chronicity, impaired control over drug use, compulsive use, continued use despite harm, and craving.

      2. Drug abuse is a maladaptive pattern of substance use characterized by repeated adverse consequences related to the repeated use of the substance. Examples include failure to fulfill important obligations at work, school, or home; repeated use creating physical danger, such as driving under the influence; legal problems; and social or interpersonal problems such as arguments and fights.

      3. Physical dependence is a state of adaptation that is manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

      4. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

EPIDEMIOLOGY

National Survey on Drug Use and Health

The National Survey on Drug Use and Health (NSDUH)¹³ is the primary source of statistical information on the use of illegal drugs by the U.S. population. Conducted by the federal government since 1971, the survey collects data from a representative sample of the population at their place of residence.

In 2011, it was estimated 22.5 million Americans aged 12 or older were current illicit drug users, which was defined by using an illicit drug during the month prior to the survey interview. This survey also found that marijuana continues to be the most commonly used illicit drug and has increased from 17.4 million past month users in 2010 to 18.1 million past month users in 2011. About 6.1 million Americans (2.4% of the population) admitted they abused prescription drugs in the past month in 2011, which is slightly lower than the 2010 data (7 million Americans), but still a monumental problem in our country.¹³

Monitoring the Future Study

Every year the Institute for Social Research at the University of Michigan conducts its Monitoring the Future Study (MTFS), supported under a series of research grants from the National Institute on Drug Abuse.¹⁴

A main purpose of this research is to study changes in the beliefs, attitudes, and behavior of young people in the United States, which requires frequent reassessment to identify the rapidly changing patterns.¹⁴

The 2012 samples included 45,449 students located in 395 secondary schools.¹⁴ After 4 straight years of increasing use among teens, annual marijuana use showed no further increase in any of the three grades surveyed in 2012. The 2012 annual prevalence rates (i.e., percent using in the prior 12 months) were 11%, 28%, and 36% for 8th, 10th, and 12th graders, respectively.

Daily use of marijuana, which had also been rising in all three grades in recent years, remained essentially flat between 2011 and 2012 at relatively high levels. The recent increases have been substantial—up by one quarter to one-third compared with their low points reached between 2006 and 2008 for the three grades. Today 1 in every 15 high school seniors (6.5%) is a daily or near-daily marijuana user. Researchers postulate that the increase of smoking marijuana is partly attributable to the national debate over medical use of cannabis, which may make the drugs seem safer to teenagers.¹⁴

Synthetic marijuana (see below) that contains designer chemicals included in the cannabinoid family (common names are K2, Spice, and Blaze) has been of increasing concern because of both its adverse effects and its high rates of use, first documented by this study in 2011. The annual prevalence rate held level among 12th graders in 2012—the second year of measurement—at 11.3%. Synthetic marijuana use was measured for the first time this year in 8th and 10th grades, and their annual prevalence rates were 4.4% and 8.8%, respectively. Aside from alcohol and tobacco, this is the second most widely used drug among 10th and 12th graders after marijuana, and the third most widely used among 8th graders after marijuana and inhalants.¹⁴

Illicit or street drug use has declined over the past decade (when marijuana use is not factored in). Unfortunately, the gradual decline has leveled off since 2010, and use has remained steady rather than declining when comparing 2011 data with 2008 data. The abuse of prescription drugs including sedatives, tranquilizers, and narcotic drugs other than heroin (most of which are analgesics) also continues to be a problem within this population group even though use has remained steady at 15.2% since 2008. Even though the use of these agents is not currently increasing in this specific population, they continue to be an important part of the nation’s drug abuse problem.¹⁴

Substance Abuse Emergencies: The DAWN Program

Since the early 1970s, the Drug Abuse Warning Network (DAWN),¹⁵ an ongoing national survey of hospital emergency departments (EDs), has collected information on patients seeking hospital ED treatment related to their use of an illegal drug or the nonmedical use of a legal drug. These data allow healthcare professionals to be better prepared to react to medical emergencies arising from illegal drug use and to target prevention and education programs to specific drug-using groups or populations.¹⁵

DAWN defines a drug-related episode as an ED visit that was induced by or related to the use of an illegal drug(s) or the nonmedical use of a legal drug for patients aged 6 to 97 years. In 2010, hospitals in the United States delivered a total of 136.1 million ED visits,¹⁶ and DAWN estimates that 2,201,050 ED visits were associated with drug misuse or abuse. This is a 94% increase since 2004—2.5 million visits in 2004 in comparison to 4.9 million visits in 2010.¹⁵ Of those ED visits, some key findings include the following:

      1. 23.8% involved illicit drugs only

      2. 27.4% involved pharmaceuticals only

      3. 3.8% involved alcohol only in patients under the age of 21

      4. 11.5% involved alcohol with other drugs

ECONOMIC IMPACT OF SUBSTANCE ABUSE

Substance abuse and addiction have an enormous impact on the economy. Over the years, the National Center on Addiction and Substance Abuse (CASA) at Columbia University has conducted studies aimed at quantifying the costs to local, state, and federal governments and agencies. The most recent figures¹⁷ are based on 2005 spending because that was the most recent year for which data were available over the course of the latest study.

Substance abuse and addiction cost federal, state, and local governments at least $467.7 billion in 2005 alone. The CASA report found that of $373.9 billion in federal and state spending, 95.6% ($357.4 billion) went to “shovel up the consequences and human wreckage of substance abuse and addiction”¹⁷; only 1.9% went to prevention and treatment, 0.4% to research, 1.4% to taxation and regulation, and 0.7% to interdiction.

ACUTE VERSUS CHRONIC PROBLEMS

Misuse of chemical substances causes problems of two types: those that occur acutely and those that arise after continued use of a drug. Acute problems are usually predictable, given the pharmacology of the drug. Chronic abuse of chemical substances can cause a wide array of physical, psychological, and psychiatric morbidities. The substance-induced disorders discussed here mainly include intoxication and withdrawal.

The essential feature of substance dependence is the continued use of the substance despite adverse substance-related problems. The criteria for substance dependence are the same for each of the drugs or drug classes, varying only to fit the unique pharmacologic properties of each drug. Patients who take prescribed drugs for appropriate medical indications and in correct doses may still show tolerance, physical dependence, and withdrawal symptoms if the drug is stopped abruptly rather than being tapered. Tolerance and physical dependence are inevitable consequences of chronic treatment with opioids and certain other drugs, but by themselves, tolerance and physical dependence do not imply “addiction.” To meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria¹⁸ for the diagnosis of substance dependence, at least three of the following must be present at any time in a 12-month period:

      1. Tolerance.

      2. Withdrawal, indicated by the appearance of the characteristic withdrawal syndrome or the use of the same or related drug to relieve or avoid withdrawal symptoms.

      3. Substance is taken in larger amounts or over a longer period of time than was intended.

      4. Patient has a persistent desire or unsuccessful efforts to cut down or control substance use.

      5. Considerable time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects.

      6. Social, occupational, or recreational activities are given up or reduced because of substance use.

      7. Substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem caused or exacerbated by the substance.

The characteristic feature of substance abuse is a maladaptive pattern of substance use indicated by repeated adverse consequences related to the repeated use of the substance.¹⁸ Examples include failure to fulfill important obligations at work, school, or home; repeated use in situations in which it is physically dangerous, such as driving under the influence; legal problems; and social or interpersonal problems such as arguments and fights.¹⁸ Intoxication refers to the development of a substance-specific syndrome after recent ingestion and presence in the body of a substance, and it is associated with maladaptive behavior during the waking state caused by the effect of the substance on the CNS. Examples include belligerence, mood lability, impaired judgment, and impaired social or occupational functioning. Evidence for recent intake of the substance can be obtained from the history, physical examination, or laboratory examination. The most common changes involve disturbances in perception, wakefulness, attention, thinking, judgment, motor behavior, and interpersonal behavior.

As with most illnesses, the course and prognosis of the disorders of substance use and dependence are variable. Getting patients who are drug dependent to stop using drugs is very difficult, and many patients return to drug use even after treatment. It has been reported that as many as 75% of treated, substance-dependent patients will relapse at least once. Many patients, however, are able to obtain recovery with treatment and continued care in 12-step programs such as Alcoholics Anonymous or Narcotics Anonymous (NA). Substance dependence or addiction can be viewed as a chronic illness that can be controlled successfully with treatment but cannot be cured and is associated with a high relapse rate. Without treatment, the course can progress to life-threatening severity, resulting from the effects of the drug, drug contaminants, or medical complications of use.¹⁸ Recently, the definitions used in the DSM-IV-TR criteria have been criticized.¹⁹ Although an in-depth discussion of the mechanism of drug addiction is beyond the scope of this chapter, the interested reader is directed to a review article that presents the current understanding of the biology of drug addiction.²⁰

CNS DEPRESSANTS

Opiates and Opioids

Deaths from prescription opioids have reached epidemic levels in the past decade. The number of overdose deaths is now greater than those of deaths from heroin and cocaine combined. In 2010, about 12 million Americans (age 12 or older) reported nonmedical use of narcotic analgesics in the past year. Nearly one third of people aged 12 and over who used drugs for the first time in 2009 began by using a prescription drug nonmedically.²¹ The Centers for Disease Control and Prevention (CDC) recently noted that, between 1997 and 2007, drug company distribution of prescription opioid analgesics increased 627%. The quantity of prescription painkillers sold to pharmacies, hospitals, and doctors’ offices was four times larger in 2010 than in 1999. According to the CDC, current distribution levels would allow “for every American to take 5 mg of Vicodin every 4 hours for 3 weeks.”²² Stated alternatively, enough prescription opioids were prescribed in 2010 to medicate every American adult around-the-clock for a month.²¹ Distribution by drug companies rose from 96 mg/person in 1997 to 698 mg/person in 2007. Although most of these drugs were prescribed for a medical purpose, many ended up in the hands of people who misused or abused them. Medical users in the last month numbered 9 million, while nonmedical users totaled 5.3 million.²²

Nearly 15,000 people die every year of overdoses involving opioid analgesics. This is more than three times the people killed by these drugs in 1999. Nearly half a million ED visits in 2009 were due to people misusing or abusing prescription painkillers. For every overdose death there are 3 abuse treatment admissions, 35 ED visits for misuse or abuse, 161 people with abuse/dependence, and 461 nonmedical users. Nonmedical use of opioid analgesics costs health insurers up to $72.5 billion annually in direct healthcare costs.²²

In the year 2000, retail pharmacies dispensed 174 million prescriptions for opioids, and by 2009, 257 million prescriptions were dispensed, which is an increase of 48%.²³

Many states report problems with “pill mills,” where doctors prescribe large quantities of opioids to people without medical justification. Some people also obtain prescriptions from multiple prescribers by “doctor shopping.”

Clinical Controversy…

Some states have a bigger problem with diversion and abuse of opioid analgesics than others. Prescription painkiller sales per person were more than three times higher in Florida, which has the highest rate, in comparison to Illinois, which has the lowest rate. From 2003 to 2009, a total of 16,550 drug overdose deaths were recorded by Florida medical examiners. The annual number of deaths increased 61%, from 1,804 to 2,905, and the death rate increased 47.5%, from 10.6 to 15.7 per 100,000 population. In 2009, approximately eight drug overdose deaths occurred each day. During 2003 to 2009, 85.9% of drug overdose deaths were unintentional, 11.1% were suicides, 2.6% were of undetermined intent, and 0.4% were homicides or pending. Prescription medications were implicated in 76.1% of all drug overdose deaths.²⁴ Further, opiate overdoses, once almost always due to heroin use, are now increasingly due to abuse of prescription painkillers.²⁵

Nearly every state has authorized prescription drug monitoring programs (PDMPs), and most are operational at this time. PDMPs are electronic systems for the monitoring of controlled substances and drugs of concern dispensed in the state or dispensed to an address in the state. They aim to detect and prevent the diversion and abuse of prescription drugs at the retail level, where no other automated information collection system exists, and to allow for the collection and analysis of prescription data more efficiently than states without such a program can accomplish.

The NSDUH indicated that illicit drug use is 16.2% among pregnant teens and 7.4% among pregnant women aged 18 to 25 years.¹³ Accordingly, in 2009, there were more than 13,000 babies born with neonatal abstinence syndrome (NAS) after being exposed to opioids in utero, a threefold increase since 2000.²⁶ Between 2000 and 2009, the incidence of NAS among newborns increased from 1.20 (95% CI, 1.04 to 1.37) to 3.39 (95% CI, 3.12 to 3.67) per 1,000 hospital births per year. Antepartum maternal opiate use also increased from 1.19 to 5.63 (per 1,000 hospital births per year). In 2009, newborns with NAS were more likely than all other hospital births to have low birth weight (19.1% vs. 7%), and respiratory complications (30.9% vs. 8.9%), and to be covered by Medicaid (78.1% vs. 45.5%). Mean hospital charges for discharges with NAS increased from $39,400 in 2000 to $53,400 in 2009. By 2009, 77.6% of charges for NAS were billed to state Medicaid programs.

Methadone

More than 30% of prescription opioid deaths involve methadone, even though only 2% of painkiller prescriptions are for this drug.²⁷

Studies using medical examiner data suggested that more than three quarters of methadone overdoses involved persons who were not enrolled in programs treating opioid addiction with methadone and that most persons who overdosed were using it without a prescription.²⁷ Recent analyses have shown that methadone was involved in one in three opioid-related deaths in 2008.²⁸ Analysis of ED data^29,30 indicates that the estimated number of ED visits resulting from nonmedical use of methadone alone or in combination with other drugs in 2009 (n = 63,031) was significantly greater than the estimated number in 2004 (n = 36,806).

Six times as many people died of methadone overdoses in 2009 than a decade before.³¹ More than 4 million methadone prescriptions were written for pain in 2009, despite US FDA warnings about the risks associated with methadone.

Methadone has pharmacologic properties unique among opioids, and as a result, a lack of knowledge about methadone among practitioners and patients has been identified as a factor contributing to the increased number of deaths observed in recent years.³² Methadone’s elimination half-life (8 to 59 hours) is longer than its duration of analgesic action (4 to 8 hours). In an FDA advisory issued in November 2006,³³ healthcare professionals were reminded that methadone’s peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. The advisory notes that during treatment initiation, methadone’s full analgesic effect is usually not attained until 3 to 5 days of dosing.

Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists to methadone. It is critical to understand the pharmacokinetics of methadone when converting patients from other opioids to methadone. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose adjustments. Also, there are pharmacokinetic and pharmacodynamic drug interactions between methadone and many other drugs. Thus, drugs administered concomitantly with methadone should be evaluated for interaction potential.³³

Benzodiazepines and Other Sedative–Hypnotics

ED visits involving benzodiazepines clearly outnumber those involving any of the other types of psychotherapeutic agents. DAWN estimates that 408,021 ED visits associated with nonmedical use of pharmaceuticals involved benzodiazepines in 2010.¹⁵ This is a dramatic increase from 2004 in which there were 170,471 ED visits attributed to benzodiazepines.

Because all benzodiazepines have abuse and dependence liability, patients cannot be switched from one benzodiazepine to another in hopes of decreasing a pattern of drug abuse or dependence behavior. Zolpidem, a nonbenzodiazepine, nonbarbiturate sedative, has been suggested to have little liability for physical dependence, but tolerance and withdrawal have been reported in association with its use as well.¹⁵ Recent reports in the lay press have linked use of zolpidem to sleep walking, erratic driving, binge eating, and other similarly bizarre activities.

CLINICAL PRESENTATION Benzodiazepine Intoxication and Withdrawal

Benzodiazepines generally do not cause life-threatening respiratory depression (unless taken with other sedatives), as do the barbiturate-like drugs.¹⁶ Long-term use of even therapeutic doses of benzodiazepines can cause physical dependence and withdrawal symptoms after abrupt discontinuation.¹⁶ Occurrence of hallucinations or seizures would indicate severe physical withdrawal.

Gradual tapering of dosage is also associated with less withdrawal and rebound anxiety than abrupt discontinuation. Dependence on sedative–hypnotics and benzodiazepines is summarized in Table 48-1. For additional information on benzodiazepine withdrawal, refer to Chapter 53.

Carisoprodol

Carisoprodol is a prescription drug marketed since 1959 and used in primary care settings for the treatment of musculoskeletal conditions associated with muscle spasms and back pain. Its effectiveness for this use has been questioned.³⁵ It is marketed in the United States as Soma as well as many generic versions. It is both structurally and pharmacologically related to meprobamate, a Schedule IV substance. In fact, a substantial percentage of the drug is metabolized to meprobamate,³⁵ a drug with barbiturate-like properties.

In legitimate medical practice, carisoprodol is used as an adjunct to rest, physical therapy, and other measures for relief of acute, painful musculoskeletal conditions.³⁵ Adverse effects are mostly related to the CNS: drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, and insomnia. Carisoprodol may also adversely affect cardiovascular (tachycardia, postural hypotension, and facial flushing), GI (nausea, vomiting, hiccup, and epigastric distress), and hematologic systems. Carisoprodol overdose has resulted in stupor, coma, shock, respiratory depression, and death.³⁵

Recognizing that prolonged abuse of carisoprodol at high dosage can lead to tolerance, dependence, and withdrawal symptoms in humans,³⁶ U.S. Drug Enforcement Administration (DEA) issued a final rule to classify carisoprodol as a Schedule IV Controlled Substance effective January 11, 2012.³⁶

The number of carisoprodol-related ED visits involving misuse or abuse by patients aged 50 or older tripled between 2004 and 2009 (from 2,070 to 7,115 visits). The majority of ED visits involving carisoprodol also involved other pharmaceuticals (77%); the most common combinations involved narcotic pain relievers (55%) and benzodiazepines (47%).¹⁵

Dextromethorphan

Dextromethorphan abuse is one of the most common (and most dangerous) examples of nonprescription drug abuse.³⁷ Intoxication from consuming large doses of cough syrup is known on the street as “robodosing” or “robotripping.” Handsful of cough and cold remedies are sometimes called “skittles” because they look similar to the popular fruit candy. Dextromethorphan creates a depressant and sometimes profound hallucinogenic effect when taken in large doses. Since it is a nonprescription drug, it is easily procured by adolescents. Those who use the cough syrup to get high are sometimes called “syrup heads.”

High doses induce effects that include hyperexcitability, lethargy, ataxia, slurred speech, diaphoresis, hypertension, nystagmus, and mydriasis. When taken at much higher doses, it acts as a dissociative anesthetic, similar to phencyclidine (PCP, “angel dust”) and ketamine (“Special K”). These are the effects sought by those who use the drug to get high. At these high doses, dextromethorphan also is a CNS depressant.³⁷

The recommended treatment for acute overdoses of dextromethorphan is naloxone. Although reports of its efficacy are mixed, it may be helpful in reversing the CNS depressant and neurologic effects.³⁸

CNS STIMULANTS

Cocaine

Cocaine is perhaps the most behaviorally reinforcing of all drugs of abuse. Clinicians estimate that approximately 10% of people who begin to use the drug recreationally will go on to serious, heavy use. Once having tried cocaine, an individual cannot predict or control the extent to which he or she will continue to use the drug.

The most characteristic pharmacologic effect of cocaine is stimulation of the CNS. In the CNS, cocaine appears to mediate its effects primarily by blocking reuptake of catecholamine neurotransmitters such as norepinephrine and dopamine.

Cocaine is absorbed rapidly from virtually all sites of application. For many years, cocaine has been administered as the hydrochloride salt form, usually by inhalation, but also by injection. In the last 18 to 20 years, as the purity of cocaine hydrochloride obtained on the street declined, many users converted the cocaine hydrochloride to cocaine base, also known as “crack” or “rock.” Smoking the drug leads to almost instant absorption and intense euphoria. Peak plasma concentrations of more than 900 ng/mL (mcg/L; 3 μmol/L) have been achieved following inhalation of cocaine base vapors, compared with concentrations of only 150 to 200 ng/mL (mcg/L; 0.49 to 0.66 μmol/L) achieved after inhalation of similar amounts of pure cocaine hydrochloride powder.³⁹ The high from snorting can last 15 to 30 minutes, whereas that from smoking can last 5 to 10 minutes. Increased use can reduce the period of stimulation. An appreciable tolerance to the high can develop, and many addicts report that they seek but fail to achieve as much pleasure as they did from their first exposure. Scientific evidence suggests that the powerful neuropsychological reinforcing property of cocaine is responsible for an individual’s continued use despite harmful physical and social consequences.

Research has helped clarify certain patterns of cocaine use, such as combining cocaine and alcohol. Such drug use would seem counterintuitive because cocaine is a CNS stimulant, and alcohol a CNS depressant. In the presence of alcohol, cocaine is metabolized to cocaethylene, a longer-acting but potent psychoactive compound compared with the parent drug.⁴⁰ The risk of death from cocaethylene is greater than from cocaine.⁴¹ The cocaine–alcohol combination is one of the most commonly identified among individuals who come to hospital EDs with acute substance abuse problems.

Cocaine is metabolized and eliminated rapidly. The elimination half-life of cocaine is approximately 1 hour, and the duration of effect is very short.³⁹ The short duration of effect provides a powerful incentive for repeated use of the drug. Many users experience intense drug use cycling, sometimes lasting days, characterized by rapidly repeating doses of cocaine until their supply is exhausted. Laboratory monkeys, given a choice between food and cocaine around-the-clock for 8 days, consistently choose cocaine.

Complications of cocaine use frequently involve cardiovascular events.^42,43 Cocaine is a psychotomimetic drug, sometimes even at nontoxic doses. A kindling phenomenon has been described with cocaine in which neuronal function becomes altered with each dose of the drug. The psychosis is qualitatively very similar to a paranoid schizophrenic psychosis.⁴⁴ Although there is some controversy as to whether cocaine is associated with physical withdrawal on abrupt discontinuation, most clinicians feel that there is a characteristic syndrome of withdrawal effects, although they are not life-threatening.

Amphetamine, Methamphetamine, and Other Stimulants

The physiologic and psychological effects of amphetamines and other stimulants are qualitatively similar to those of cocaine—they diminish fatigue, increase alertness, and suppress appetite. Pharmacologically, amphetamines increase the activity of catecholamine neurotransmitters (e.g., norepinephrine and dopamine) by increasing release and by inhibiting the degradative enzyme monoamine oxidase.³⁶

Methamphetamine is used orally, intranasally, rectally, by IV injection, and by smoking. Immediately after inhalation or IV injection, the methamphetamine user experiences an intense sensation, called a “rush” or “flash,” that lasts only a few minutes and is described as extremely pleasurable.

Because methamphetamine elevates mood, people who experiment with it tend to use it with increasing frequency and in increasing doses, although this was not their original intent. The timing and intensity of the “rush” that accompanies the use of methamphetamine, which is a result of the release of high levels of dopamine in the brain, depend in part on the method of administration. Specifically, the effect is almost instantaneous when smoked or injected, whereas it takes approximately 5 minutes after snorting or 20 minutes after oral ingestion. Prolonged use of methamphetamine can result in a tolerance for the drug and increased use at higher dosage levels, creating dependence. Such continual use of the drug with little or no sleep may lead to an extremely irritable and paranoid state. Discontinuing use of methamphetamine often results in a state of depression, as well as fatigue, anergia, and some types of cognitive impairment that can last from 2 days to several months.

Negative consequences of methamphetamine abuse range from anxiety and insomnia to convulsions, paranoia, and brain damage. Methamphetamine-induced caries, or “meth mouth,” is a characteristic pattern of dental decay commonly observed in patients who smoke methamphetamine.⁴⁵

In addition to the many direct effects on methamphetamine users are the indirect impacts on individuals and society. Flammable ingredients that include acetone, red phosphorous, ethyl alcohol, and lithium metal are used in methamphetamine cookers, often with disastrous results. Fires and explosions often ensue, resulting in severe burns and uncovering laboratories to local law enforcement. Children of methamphetamine abusers are at high risk of neglect and abuse, and pregnant women’s use of methamphetamine can cause growth retardation, premature birth, and developmental disorders in neonates. Treatment for methamphetamine dependence is very difficult, and has a low success rate.⁴⁶ The expanding global market is fed by an increase in clandestine manufacture of methamphetamine. Not only are there more laboratories in more countries, but their size and sophistication are also increasing. The number of reported domestic methamphetamine laboratory seizures in 2010 (6,768) represents a 12% increase over the total number of methamphetamine laboratories seized in 2009 (6,032).⁴⁶ An increasing number of methamphetamine laboratories seized in the United States are small-scale operations capable of producing less than 2 oz (about 60 g) of the drug per production cycle. At least 81% of the laboratories seized every year since 2006 were small-scale. Most of the remaining laboratories seized were also relatively small, with capacities between 2 and 8 oz (about 60 and 230 g) per production cycle.⁴⁶