3575Cocaine, Other Psychostimulants, and Hallucinogens CHAPTER 457

substances have been noted as contaminants of psychostimulants.

Levamisole, an anthelminthic and immunomodulator used primarily

in veterinary medicine, has been found in cocaine and can cause agranulocytosis, leukoencephalopathy, and cutaneous vasculitis, which has 

pioid Agonist Medications For Maintenance Methadone

maintenance substitutes a once-daily oral opioid dose for three to four

times daily heroin. Methadone saturates the opioid receptors and, by

inducing a high level of opioid tolerance, blocks the euphoria from

additional opioids. Buprenorphine, a partial opioid agonist, also can be

given once daily at sublingual doses of 4–32 mg daily, and in contrast

to methadone, it can be given in an office-based primary care setting.

METHADONE MAINTENANCE Methadone’s slow onset of action when

taken orally, long elimination half-life (24–36 h), and production of

cross-tolerance at doses from 80 to 150 mg are the basis for its efficacy

in treatment retention and reductions in IV drug use, criminal activity,

and HIV risk behaviors and mortality. Methadone can prolong the QT

interval at rates as high as 16% above the rates in non-methadonemaintained, drug-injecting patients, but it has been used safely in the

treatment of opioid use disorder for 40 years.

BUPRENORPHINE MAINTENANCE While France and Australia have

had sublingual buprenorphine maintenance since 1996, it was first

approved by the U.S. Food and Drug Administration (FDA) in 2002 as

a Schedule III drug for managing opioid use disorder. Unlike the full

agonist methadone, buprenorphine is a partial agonist of mu-opioid

receptors with a slow onset and long duration of action. 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,

and many patients in methadone maintenance require higher doses of

up to 150 mg daily. Buprenorphine is combined with naloxone at a 4:1

ratio in order to reduce its abuse liability. Because of pediatric exposures and diversion of buprenorphine to illicit use, a new formulation,

using mucosal films rather than sublingual pills that were crushed and

snorted, is now marketed. A subcutaneous buprenorphine implant

that lasts up to 6 months has FDA approval as a formulation to prevent

pediatric exposures and illicit diversion and to enhance compliance.

In the United States, the ability of primary care physicians to prescribe buprenorphine for opioid use disorder represents an important

opportunity to improve access and quality of treatment as well as

reduce social harm. Europe, Asia, and Australia have found reduced

opioid-related deaths and drug-injection-related medical morbidity

with buprenorphine available in primary care. Retention in officebased buprenorphine treatment has been as high as 70% at 6-month

follow-ups.

Opioid Antagonist Medications The rationale for using narcotic

antagonist therapy is that blocking the action of self-administered opioids should eventually extinguish the habit, but this therapy is poorly

accepted by patients. Naltrexone, a long-acting orally active pure opioid antagonist, can be given three times a week at doses of 100–150 mg.

Because it is an antagonist, the patient must first be detoxified from

opioids before starting naltrexone. It is safe even when taken chronically for years, 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 naltrexone if liver function tests are three

times above normal levels. Naltrexone maintenance combined with

psychosocial therapy is effective in reducing heroin use, but medication

adherence is low. 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.

In the United States, a depot naltrexone formulation is available for

monthly use and maintains blood levels equivalent to 25 mg of daily

oral use.

Medication-Free Treatment Most opioid users enter medication-free treatments in inpatient, residential, or outpatient settings, but

1- to 5-year outcomes are very poor compared to pharmacotherapy

except for residential settings lasting 6–18 months. The residential

programs require full immersion in a regimented system with progressively increasing levels of independence and responsibility within

a controlled community of fellow drug users. These medication-free

programs, as well as the pharmacotherapy programs, also include

counseling and behavioral treatments designed to teach interpersonal

and cognitive skills for coping with stress and for avoiding situations

leading to easy access to drugs or to craving. Relapse is prevented by

having the individual very gradually reintroduced to greater responsibilities and to the working environment outside of the protected

therapeutic community.

■ PREVENTION

Preventing the development of opioid use disorder represents a critically important challenge for physicians. Opioid prescriptions are the

most common source of drugs accessed by adolescents who begin a

pattern of illicit drug use. The major sources of these drugs are family

members, not drug dealers or the Internet. Pain management involves

providing sufficient opioids to relieve the pain over as short a time as

the pain warrants (Chap. 13). The patient then needs to dispose of any

remaining opioids, not save them in the medicine cabinet, because this

behavior leads to diversion by adolescents. Finally, physicians should

never prescribe opioids for themselves.

■ FURTHER READING

Blanco C, Volkow ND: Management of opioid use disorder in the

USA: Present status and future directions. Lancet 393:1760, 2019.

Griesler PC et al: Medical use and misuse of prescription opioids in

the US adult population: 2016-2017. Am J Public Health 109:1258,

2019.

Wakeman SE et al: Comparative effectiveness of different treatment

pathways for opioid use disorder. JAMA Netw Open 3:e1920622,

2020.

3573Cocaine, Other Psychostimulants, and Hallucinogens CHAPTER 457

The use of cocaine, methamphetamine, other psychostimulants, and

hallucinogens reflects a complex interaction between the pharmacology of the drug, the personality and expectations of the user, and the

environmental context in which the drug is used. These substances

cause significant harm, although they are less commonly used than

other addictive substances such as alcohol (Chap. 453), nicotine

(Chap. 454), cannabis (Chap. 455), and opioids (Chap. 456). It is also

important to recognize that polydrug use, involving the concurrent

use of several drugs with different pharmacologic effects, is common.

Sometimes one drug is used to enhance the effects of another, as with

the combined use of cocaine and nicotine, or cocaine and heroin in

methadone-treated patients. Some forms of polydrug use, such as the

combined use of intravenous (IV) heroin and cocaine, are especially

dangerous and account for many hospital emergency department

visits. Cocaine and psychostimulant use (especially chronic patterns

of use) may cause adverse health consequences and exacerbate preexisting disorders such as hypertension and cardiac disease. In addition,

the combined use of two or more drugs may accentuate medical complications associated with use of one drug. Chronic use is often associated with immune system dysfunction and increased vulnerability

to infections, including risk for HIV infection. The concurrent use of

cocaine and opiates (“speedball”) is frequently associated with needle

sharing by people using drugs intravenously. People who use IV drugs

represent the largest single group of individuals with HIV infection

in several major metropolitan areas in the United States as well as in

many parts of Europe and Asia. Furthermore, several outbreaks of HIV

in the United States since 2015 in rural and suburban areas have been

attributed to clusters of injection drug use.

Psychostimulants and hallucinogens have been used for centuries to

induce euphoria and alter consciousness. Hallucinogens have become

popular recently, and new drugs are continually being developed.

This chapter describes the subjective and adverse medical effects

of cocaine, other psychostimulants including methamphetamine,

3,4-methylenedioxymethamphetamine (MDMA), and cathinones;

hallucinogens such as phencyclidine (PCP), d-lysergic acid diethylamide (LSD), and Salvia divinorum; and emerging drugs.

PSYCHOSTIMULANTS

Psychostimulants include cocaine and methamphetamine, as well as

drugs with stimulant-like properties such as MDMA and cathinones.

In addition, prescribed psychostimulants such as methylphenidate,

dextroamphetamine, and amphetamine are considered here.

■ COCAINE

Cocaine is a powerful psychostimulant drug made from the cocoa

plant. It has local anesthetic, vasoconstrictor, and stimulant properties.

Cocaine is a Schedule II drug, which means that it has high potential

for abuse but can be administered by a physician for legitimate medical

uses, such as local anesthesia for some eye, ear, and throat surgeries.

Pharmacology Cocaine comes in a variety of forms, the most-used

being the hydrochloride salt, sulfate, and a base. The salt is an acidic,

water-soluble powder with a high melting point, used by snorting or

sniffing intranasally or by dissolving it in water and injecting it. When

used intranasally the bioavailability of cocaine is about 60%. Cocaine

sulfate (“paste”) has a melting point of almost 200°C, so it has limited

use, but is sometimes smoked with tobacco. The base form can be

freebase or crystallized as crack. Cocaine freebase is made by adding

a strong base to an aqueous solution of cocaine and extracting the

alkaline freebase precipitate. It has a melting point of 98°C and can be

457

vaporized and inhaled. Freebase cocaine can also be crystallized and

sold as crack or rock, which is also smoked or inhaled. Street dealers

often dilute (or “cut”) cocaine with nonpsychoactive substances such as

cornstarch, talcum powder, flour, or baking soda, or adulterate it with

other substances with similar effects (like procaine or amphetamine)

to increase their profits. A recent concern has been the adulteration

of cocaine (and other psychostimulants) with fentanyl-related opioids,

resulting in overdose deaths due to opioid effects or polydrug use.

Given the extensive pulmonary vasculature, smoked or vaporized

cocaine reaches the brain very quickly, similar in speed of onset to

injected cocaine. The result is a rapid, intense, transient high, which

enhances its addictive potential. Cocaine binds to the dopamine (DA)

transporter and blocks DA reuptake, which increases synaptic levels

of the monoamine neurotransmitters DA, norepinephrine (NE), and

serotonin (5HT), in both the central nervous system (CNS) and the

peripheral nervous system (PNS). Use of cocaine, like other drugs of

abuse, induces long-term changes in the brain. Animal studies have

shown adaptations in neurons that release the excitatory neurotransmitter glutamate after cocaine exposure.

Epidemiology According to the National Survey on Drug Use

and Health (NSDUH), in 2019 an estimated 5.5 million people aged

12 years or older (2.0% of the population) were past-year consumers of

cocaine, including about 778,000 (0.3% of the population) consumers

of crack. Among those, 671,000 used cocaine for the first time (1800

cocaine initiates/day) including 59,000 adolescents aged 12–17 years.

About 1 million people aged 12 years or older (0.4% of the population)

in 2019 had a cocaine use disorder, but fewer than 1 in 5 received

treatment, in the past year. According to the CDC National Center for

Health Statistics, drug overdose deaths involving cocaine rose from

3822 in 1999 to 15,833 in 2019, with continued increases projected

in 2020. Cocaine was involved in more than 1 in 5 overdose deaths in

2019. The number of deaths in combination with any opioid has been

increasing steadily since 2014 and is mainly driven by the involvement

of synthetic opioids including fentanyl and fentanyl analogs.

■ METHAMPHETAMINE

Methamphetamine is a psychostimulant drug usually used as a white,

bitter-tasting powder or a pill. Crystal methamphetamine is a form of

the drug that looks like glass fragments or shiny, bluish-white rocks.

It can be inhaled/smoked, swallowed (pill), snorted, or injected (after

being dissolved in water or alcohol).

Pharmacology When smoked, methamphetamine exhibits 90.3%

bioavailability, compared to 67.2% for oral ingestion. Methamphetamine

exists in two stereoisomers, the l- and d-forms. d-Methamphetamine,

or the dextrorotatory enantiomer, is a more powerful psychostimulant,

with 3–5 times the CNS activity as compared with l-methamphetamine. Methamphetamine is a cationic lipophilic molecule, which

stimulates the release, and partially blocks the reuptake, of newly

synthesized catecholamines in the CNS. Methamphetamine has a

similar structure to the DA, NE, 5HT, and vesicular monoamine transporters and reverses their endogenous function, resulting in release

of monoamines from storage vesicles into the synapse. Methamphetamine also attenuates the metabolism of monoamines by inhibiting

monoamine oxidase.

Methamphetamine is more potent than amphetamine, resulting in

much higher concentrations of synaptic DA and more toxic effects

on nerve terminals. Outside the medical context, methamphetamine’s

pharmacokinetics and low cost often result in a chronic and continuous, high-dose self-administered use pattern.

Epidemiology According to the NSDUH, in 2019 approximately

2 million people aged 12 years or older (0.7% of the population) used

methamphetamine in the past year, of those 184,000 used methamphetamine for the first time (510 people per day), and about 25%

reported injecting methamphetamine. In 2019, an estimated 1 million

people aged 12 years or older (0.4% of the population and 50% of those

with past-year use) had a methamphetamine use disorder. High rates

of co-occurring substance use or mental illness exist in adults who

Cocaine, Other

Psychostimulants, and

Hallucinogens

Karran A. Phillips, Wilson M. Compton

3574 PART 13 Neurologic Disorders

use methamphetamine and only about one-third of adults with pastyear methamphetamine use disorder received addiction treatment.

Methamphetamine availability and methamphetamine-related harms

(overdose deaths, treatment admissions, infectious disease transmission, etc.) continue to increase in the United States. According to

CDC data, psychostimulants with abuse potential (primarily methamphetamine) caused 16,167 overdose deaths in 2019. These substances were the second leading cause of overdose death nationwide

accounting for 23% of overdose deaths (compared to 49,860 deaths

from an opioid in 2019). Of note there is significant geographic variation in the role of methamphetamine in overdose deaths; in four

western regions methamphetamine was the #1 cause of overdose

death accounting for 21–38% of all overdose deaths. Geographic

variation is also apparent in overall psychostimulant-involved mortality rates; from 2015–2018 the highest increase was observed in

West Virginia for psychostimulant use alone. Mortality associated with

psychostimulants combined with opioids ranged from 15% in Hawaii

to 91% in New Hampshire.

■ MDMA AND CATHINONES

MDMA also known as Molly, ecstasy, or X, is an illegal synthetic drug

that has stimulant and psychedelic effects. Khât is a plant found in

East Africa and the Middle East; it has been used for centuries for

its mild stimulant-like effect. Synthetic cathinones or “bath salts” are

manufactured psychostimulants that are chemically similar to the naturally occurring substance cathinone found in the khât plant and are

discussed under “Emerging Drugs” below.

MDMA Molly, slang for “molecular,” refers to the crystalline powder form of MDMA usually sold as powder or in capsules. The content of Molly varies and is often not MDMA at all but rather contains

methylone or ethylone, which are synthetic substances commonly

found in so-called bath salts and pose significant health risks. The

clinician should always consider the possibility that the drug reported

by the user may be incorrect or contaminated with other substances.

With MDMA use, individuals experience increased physical and

mental energy, distortions in time and perception, emotional warmth,

empathy toward others, a general sense of well-being, decreased anxiety, and an enhanced enjoyment of tactile experiences. MDMA is usually taken orally in a tablet, capsule, or liquid form with first effect at

45 min on average, peak effect at 1–2 h, and duration ~3–6 h. MDMA

binds to serotonin transporters and increases the release of serotonin,

NE, and DA. Research in animals has shown that MDMA in moderate

to high doses can cause loss of serotonin-containing nerve endings

and permanent damage. MDMA is a Schedule I drug, along with other

substances with no proven therapeutic value. MDMA is currently in

clinical trials as a possible treatment for posttraumatic stress disorder

and anxiety and for patients with terminal illness including cancer. The

evidence on MDMA’s therapeutic effects is quite limited to date, and

research is ongoing.

Adulteration of MDMA tablets with methamphetamine, ketamine,

caffeine, the over-the-counter cough suppressant dextromethorphan

(DXM), the diet drug ephedrine, and cocaine is common. MDMA is

rarely used alone and is often mixed with other substances, such as

alcohol and marijuana, making the scope of its use difficult to ascertain. According to the NSDUH, >18 million people in the United States

have tried MDMA at least once in their life. MDMA is predominantly

used by men 18–25 years of age, with use typically beginning at

age 21 years. There is evidence that gay or bisexual men and women are

more likely than their heterosexual counterparts to have used MDMA

in the last 30 days.

Cathinone Is an alkaloid psychostimulant structurally similar to

amphetamine found in the khât (Catha edulis) plant, which grows at

high altitudes in East Africa and the Middle East and whose leaves are

chewed for their mild stimulant-like effect. The extraction of cathinone

and other alkaloids from the leaves by chewing is very effective leaving

little as unabsorbed residue. The leaves and twigs can also be smoked,

infused in tea, or sprinkled on food. Cathinone increases dopamine

release and reduces dopamine reuptake.

Originally limited to its area of cultivation, with advances in rapid

transportation and postal delivery khât is now available in several

continents including Europe and North America. Worldwide it is

estimated that 10 million people chew khât, including up to 80% of

all adults in some areas where the evergreen shrub is indigenous. In

regions where the plant is indigenous, there have also been reports

of khât use as a study aid among university students. Cathinone is a

Schedule I drug in the United States, making its use illegal; however,

the khât plant itself is not controlled.

■ PRESCRIBED PSYCHOSTIMULANTS

Methylphenidate, dextroamphetamine, and dextroamphetamine/

amphetamine combination products are psychostimulants approved in

the United States for treatment of attention-deficit hyperactivity disorder (ADHD), weight control, and narcolepsy. Prescription psychostimulants increase alertness, attention, and energy. Phenylpropanolamine,

a psychostimulant used primarily for weight control, was found to be

related to hemorrhagic stroke in women and removed from the market

in 2005. Nonprescribed amphetamines or methylphenidate is used

quite frequently by college students, and as an energy and productivity

booster by others. According to the 2019 NSDUH, past-year prescription stimulant misuse was reported by 4.9 million (1.8%) people aged

12 years or older. Past-year initiates of prescription stimulant misuse

totaled 901,000, which averages to about 2500 people misusing prescription stimulants for the first time each day, including 1000 young

adults each day. Among people aged 12 years or older, 0.2% (558,000

people) had a prescription stimulant use disorder in the past year.

■ PSYCHOSTIMULANT CLINICAL MANIFESTATIONS

Psychostimulants produce the same acute CNS effects: euphoria/

elevated mood, increased energy/decreased fatigue, reduced need for

sleep, decreased appetite, heightened sense of alertness, decreased distractibility, dosed-dependent effects on focus, attention, and curiosity,

increased self-confidence, increased libido, and prolonged orgasm,

independent of the specific psychostimulant or route of administration. Peripheral effects may include tremor, diaphoresis, hypertonia,

tachypnea, hyperreflexia, and hyperthermia. Many of the effects are

biphasic; for example, low doses improve psychomotor performance,

while higher doses may cause tremors or convulsions. α-adrenergically

mediated cardiovascular effects are also biphasic, with low doses

resulting in increased vagal tone and decreased heart rate, and high

doses causing increased heart rate and blood pressure. Psychostimulant

use can result in restlessness, irritability, and insomnia and, at higher

doses, suspiciousness, repetitive stereotyped behaviors, and bruxism.

Endocrine effects resulting from chronic use may include impotence,

gynecomastia, menstrual function disruptions, and persistent hyperprolactinemia (Table 457-1).

Overdose presents as sympathetic nervous system overactivity with

psychomotor agitation, hypertension, tachycardia, headache, and

mydriasis, and can lead to convulsions, cerebral hemorrhage or infarction, cardiac arrhythmias or ischemia, respiratory failure, or rhabdomyolysis. It is a medical emergency; treatment is largely symptomatic

and should occur in an intensive care or telemetry unit. Inhalation of

crack cocaine that is vaporized at high temperatures can cause airway

burns, bronchospasm, and other symptoms of pulmonary disease.

MDMA has also been shown to raise body temperature and can occasionally result in liver, kidney, or heart failure, or even death.

Psychostimulants are often used with other drugs, including opioids

and alcohol, whose CNS-depressant effects tend to attenuate psychostimulant-induced CNS stimulation. These combinations often have

additive deleterious effects, increasing the risk of morbidity and mortality. An example of this risk is the use of cocaine with alcohol, which

results in the metabolite, cocaethylene. Cocaethylene’s effects on the

cardiovascular system are additive to that of cocaine’s effects, resulting

in intensified pathophysiologic consequences.

Adulteration of psychostimulants, particularly cocaine, with

other drugs is common and can have additional potential health

consequences. In addition to contamination with fentanyl-related

compounds, potentially resulting in fatal overdose, multiple other

3575Cocaine, Other Psychostimulants, and Hallucinogens CHAPTER 457

substances have been noted as contaminants of psychostimulants.

Levamisole, an anthelminthic and immunomodulator used primarily

in veterinary medicine, has been found in cocaine and can cause agranulocytosis, leukoencephalopathy, and cutaneous vasculitis, which has

resulted in cutaneous necrosis. Clenbuterol, a sympathomimetic amine

used clinically as a bronchodilator, has also been found in cocaine and

can result in tachycardia, hyperglycemia, palpitations, and hypokalemia. Studies in Europe have found that, in addition to levamisole,

some of the most common adulterants in cocaine include phenacetin,

lidocaine, caffeine, diltiazem, hydroxyzine, procaine, tetracaine, paracetamol, creatine, and benzocaine.

Withdrawal from psychostimulants often includes hypersomnia,

increased appetite, and depressed mood. Acute withdrawal typically

lasts 7–10 days, but residual symptoms, possibly associated with neurotoxicity, may persist for several months. Debate remains whether psychostimulant withdrawal symptoms decline monotonically or occur in

discrete phases, becoming worse before they improve. Psychostimulant

withdrawal is not thought to be a major driver of ongoing use. Most

current theories of psychostimulant addiction emphasize the primary

role of conditioned craving, which can persist long after physiological

withdrawal has abated. Conditioned craving includes the urge to use

drugs in response to cues in the environment associated with drug

use, such as drug-using associates, drug paraphernalia, drug-using

locations, etc.

Injection of psychostimulants places people at increased risk

of contracting infectious diseases from exposure to HIV and hepatitis B or C in blood or other bodily fluids, as well as with skin

abscesses and endocarditis. Psychostimulant use can also increase

risk for infection by causing altered judgment and decision-making,

leading to risky behaviors, such as unprotected sex. There is some

evidence that psychostimulant use may worsen the progression of

HIV/AIDS via increased injury to nerve cells exacerbating cognitive

problems.

The actions and effects of khât are like those of other psychostimulants. Short-term effects include euphoria, increased alertness and

arousal, loss of appetite, insomnia, headaches, and tremors. Long-term

use may result in gastrointestinal disorders such as constipation, ulcers,

and stomach inflammation as well as increased risk for acute myocardial infarction and stroke, due to inotropic and chronotropic effects on

the heart, vasospasm of coronary arteries, and catecholamine-induced

platelet aggregation. There is evidence that, rarely, heavy khât use may

cause mild to moderate psychological dependence. Compulsive use

has been described, with resulting grandiose delusions, paranoia, and

hallucinations. Mild withdrawal from khât has been described and

can include depression, nightmares, low blood pressure, and lack of

energy.

■ DIAGNOSIS

The Diagnostic and Statistical Manual of Psychiatric Disorders, 5th

edition (DSM-5) defines a stimulant use disorder (SUD) as a pattern

of use of amphetamine-type substances, cocaine, or other stimulants

leading to clinically significant impairment or distress, as manifested by at least 2 of the following 11 problems within a 12-month

period: taking larger amounts, or over a longer period of time, than

intended; persistent desire or unsuccessful efforts to reduce or control use; a great deal of time spent in activities necessary to obtain,

use, or recover; craving; use resulting in failure to fulfill major role

obligations; continued use, despite recurrent social or interpersonal

problems; giving up social, occupational, or recreational activities;

recurrent use in physically hazardous situations; continued use despite

persistent or recurrent physical or psychological problems; tolerance;

and withdrawal symptoms, or avoidance of withdrawal symptoms, by

continued use.

The International Classification of Diseases (ICD) 10th Revision

(ICD-10) recognizes “stimulant dependence syndrome” and “stimulant

withdrawal state” and the ICD 11th Revision (ICD-11) further specifies the definition to “stimulant dependence including amphetamines,

methamphetamines, or methcathinone.”

TABLE 457-1 Complications of Psychostimulant Use

Cardiovascular Acute

• Arterial vasoconstriction

• Thrombosis

• Tachycardia

• Hypertension

• Increased myocardial oxygen demand

• Increased vascular shearing forces

• Coronary vasoconstriction

• Cardiac ischemia

• Left ventricular dysfunction/heart failure (high blood

concentrations)

• Supraventricular and ventricular dysrhythmias

• Aortic dissection/rupture

Chronic

• Accelerated atherogenesis

• Left ventricular hypertrophy

• Dilated cardiomyopathy

Central and Peripheral

Nervous Systems

• Hyperthermia

• Psychomotor agitation

• Tremor

• Hyperreflexia

• Hypertonia

• Headache

• Seizures

• Coma

• Intracranial hemorrhage

• Focal neurologic symptoms

Pulmonary • Angioedema (inhaled)

• Pharyngeal burns (inhaled)

• Pneumothorax

• Pneumomediastinum

• Pneumopericardium

• Reversible airway disease exacerbations

• Bronchospasm

• Shortness of breath (“crack lung”)

• Tachypnea

• Pulmonary infarction

Gastrointestinal • Perforated ulcers

• Ischemic colitis

• Bowel infarction

• Impaction (body packing)

• Hepatic enzyme elevation

Renal • Metabolic acidosis

• Renal infarction

• Rhabdomyolysis

Endocrine • Impotence

• Gynecomastia

• Menstrual function disruptions

• Hyperprolactinemia

Other • Diaphoresis

• Irritability

• Insomnia

• Bruxism

• Stereotypy

• Splenic infarction

• Acute angle-closure glaucoma

• Vasospasm of the retinal vessels (unilateral or

bilateral vision loss)

• Mydriasis

• Madarosis

• Abruptio placentae

3576 PART 13 Neurologic Disorders

TREATMENT

Acute Intoxication

As with all emergency situations the first task is to check a patient’s

airway, breathing, and circulation. With cocaine use, succinylcholine is relatively contraindicated in rapid-sequence intubation;

consider rocuronium (1 mg/kg IV) or another nondepolarizing

agent as an alternative. If psychomotor agitation occurs, rule out

hypoglycemia and hypoxemia first, and then administer benzodiazepines (e.g., diazepam 10 mg IV and then 5–10 mg IV every

3–5 min until agitation controlled). Benzodiazepines are usually

sufficient to address cardiovascular side effects. Severe or symptomatic hypertension can be treated with phentolamine, nitroglycerin,

or nitroprusside. Hyperthermic patients should be cooled within

≤30 min with the goal to achieve a core body temperature of <39°C

(102°F). Evaluation of chest pain in someone using cocaine should

include an electrocardiogram, chest radiograph, and biomarkers

to exclude myocardial infarction. The treatment approach is similar to nonstimulant-induced chest pain; however, it is recommended that whenever possible beta blockers not be used in people

who use cocaine. The concern arises from the potential unopposed alpha-adrenergic stimulation that results from beta blockade possibly causing coronary arterial vasoconstriction, ischemia,

and infarction and limited data supporting the benefit of beta

blockers in cocaine-related cardiovascular complications. If beta

blockers are to be given, it is suggested that mixed alpha/beta blockers, e.g., labetalol and carvedilol, be used rather than nonselective

beta blockers, and only in situations where the benefits outweigh

the risks. Because many instances of psychostimulant-related mortality have been associated with concurrent use of other illicit drugs

(particularly opioids), the physician must be prepared to institute

effective emergency treatment for multiple drug toxicities.

Psychostimulant Use Disorders

Treatment of stimulant use disorders requires the combined efforts

of primary care physicians, psychiatrists, and psychosocial care providers. Early abstinence from psychostimulant use is often complicated by symptoms of depression and guilt, insomnia, and anorexia,

which may be as severe as those observed in major affective disorders and can last for months and even years after use has stopped.

Behavioral therapies, including cognitive-behavioral therapy

(CBT), the community reinforcement approach (CRA), contingency management (CM; providing rewards to patients who remain

substance free), motivational enhancement therapy (MET), combinations of these, and others remain the mainstay of treatment for

stimulant use disorders and show modest benefit. These behavioral therapies are designed to help modify the patient’s thinking,

expectancies, and behaviors, and to increase life-coping skills, with

behavioral interventions to support long-term, drug-free recovery.

Based on systematic reviews, contingency management has been

noted to be particularly effective. However, the effect of these

behavioral therapies is often not sustained, and they may be less

effective in individuals with severe use disorder.

There are no U.S. Food and Drug Administration (FDA)-

approved medications for psychostimulant addiction. Current

research includes several neurotransmitter-based strategies, including DA agonist-, serotonin-, γ-aminobutyric acid (GABA)-, and

glutamate-based approaches. Trials of agonist therapy with longeracting psychostimulant medications such as dexamphetamine and

methylphenidate have not been conclusive. Studies with the antidepressants mirtazapine, bupropion, sertraline, imipramine, and

atomoxetine have been equivocal as have studies with the atypical antipsychotic, aripiprazole, and the anticonvulsant, topiramate.

Other therapies being studied for the treatment of psychostimulant

use disorder include: acamprosate (possibly via a role in Ca2+

supply), galantamine (reversible acetylcholine esterase inhibitor,

which may strengthen impulse control, as well as cognitive and social

abilities depleted by long-term psychostimulant use), naltrexone

(opiate receptor antagonist), doxazosin (alpha-adrenergic antagonist), and varenicline (partial agonist at the α4β2 nicotinic acetylcholine receptors and DA neurotransmission enhancer). Overall, it

is promising that some of the medications studied showed statistically significant outcome improvement over placebo, but many of

these studies were underpowered due to issues of small sample size,

sample bias, low participant retention, and low treatment adherence rates. Ongoing studies are investigating lisdexamfetamine

(a dexamphetamine pro-drug), a combination of extended-release

naltrexone with bupropion, pomaglumetad (a glutamate agonist),

and monoclonal antibodies. Special attention needs to be paid to

the inclusion of underrepresented populations including women

in future stimulant use disorder medication trials. Vaccines for

cocaine and methamphetamine use disorders are also being developed. Finally, recent preliminary studies have brought attention to

the potential use of brain stimulation techniques such as transcranial magnetic stimulation (TMS), theta-burst stimulation (TBS),

and transcranial direct current stimulation (tDCS) to treat psychostimulant use disorders, although further studies will be required to

determine their value, if any, in this situation.

HALLUCINOGENS

Hallucinogens are a diverse group of drugs causing alteration of

thoughts, feelings, sensations, and perceptions. Some hallucinogens

are found naturally in plants and mushrooms, while others are synthetic. They include: ayahuasca (a tea made from Amazonian plants

containing dimethyltryptamine (DMT), the primary mind-altering

ingredient); DMT (aka Dimitri, can also be synthesized in a lab);

LSD (clear or white odorless material made from lysergic acid found

in rye and other grain fungus); peyote (mescaline, derived from a

small, spineless cactus or made synthetically); and 4-phosphoryloxyN,N-dimethyltryptamine (psilocybin, comes from certain South and

North American mushrooms).

A subgroup of hallucinogens produces the added sensation of feeling

out of control or disconnected from one’s body or surroundings. These

dissociative drugs include: DXM (an over-the-counter cough suppressant, when used in high doses); ketamine (a human and veterinary

anesthetic as well as an antidepressant medication recently approved by

the FDA); phencyclidine (PCP; a cyclohexylamine derivative and dissociative anesthetic); and Salvia divinorum (salvia, a Mexican, Central,

and South American plant). Dissociative drugs distort the way the user

perceives time, motion, color, sound, and self, and their use can lead to

bizarre and dangerous behavior and cause respiratory depression, heart

rate abnormalities, and a withdrawal syndrome including drug craving,

confusion, headache, and sweating.

Use of hallucinogens in religious and spiritual rituals goes back

centuries, and they are ingested in a wide variety of ways, including

orally, by smoking, intranasally, and transmucosally. Especially when

taken orally, the onset of action of hallucinogens is within 20–90 min

and the duration of action can be as long as 6–12 h, except for salvia,

whose effects generally last about 30 min. Hallucinogens specifically

disrupt the neurotransmitters serotonin and glutamate. Effects on the

serotonin system can disturb mood, sensory perception, sleep, appetite,

body temperature, sexual behavior, and muscle control. Glutamate system effects include perturbations in pain perception, responses to the

environment, emotion, and learning and memory.

According to the NSDUH, in 2019 1.9 million adults reported

past-month hallucinogen use and 6 million (2.2% of the population)

reported past-year hallucinogen use, an increase from 4.7 million

(1.8%) in 2015. Of these, 1.2 million used hallucinogens for the first

time. These estimates are similar to 2015 and 2018 estimates for

those aged 12–17 years but reflect an increase in past-year use among

those aged 26 years and older. Of note, these statistics include ecstasy

(MDMA or “Molly”) in the overall hallucinogen use as well as LSD,

PCP, peyote, mescaline, psilocybin mushrooms, ketamine, DMT/

AMT/”Foxy”, and Salvia divinorum. New initiates to drug use per day

3577Cocaine, Other Psychostimulants, and Hallucinogens CHAPTER 457

among people age 12 years and older include 2421 for LSD, 83 for PCP,

and 2039 for ecstasy. According to 2019 Monitoring the Future Data,

the annual prevalence of use among 12th graders was 1.1% for PCP,

2.2% for ecstasy, and 0.7% for salvia, which was similar to 2018.

Clinical manifestations of hallucinogen use include false sensory

experiences (i.e., hallucinations), intensified feelings, heightened sensory experiences, and time perturbations. Additional physiologic

responses include nausea; increased heart rate, blood pressure, respiratory rate, or body temperature; loss of appetite; xerostomia; sleep

problems; synesthesia; impaired coordination; and hyperhidrosis.

Extremely negative experiences with hallucinogen use (the “bad trip”)

can include panic, paranoia, and psychosis, which may persist for up

to 24 h. Such experiences are best treated with supportive reassurance,

but benzodiazepines (e.g., diazepam 10 mg or lorazepam, if liver

damage is present) may be administered if agitation is severe. There

is some evidence that chronic effects of hallucinogen use can occur,

including persistent psychosis, memory loss, anxiety, depression, and

flashbacks. Long-term effects of PCP and other dissociative drug use

can include persistent speech difficulties, memory loss, depression,

suicidal thoughts, anxiety, and social withdrawal that may persist for a

year or more after chronic use stops.

Psilocybin is under active investigation for its possible benefit in

treatment of depression and some anxiety disorders.

Hallucinogen addiction is atypical, as use patterns are generally not

chronic, and there are currently no FDA-approved medications for the

treatment of hallucinogen addiction. Research on behavioral treatments for hallucinogen addiction is underway.

EMERGING DRUGS

With the aid of the Internet, and some basic over-the-counter (and

other) ingredients, the rise of the “kitchen chemist” is upon us. The

production of new psychoactive substances (NPSs), such as synthetic

cathinones (bath salts) and synthetic cannabinoids (spice), is on the

rise and has resulted in the use of unregulated psychoactive substances

that are intended to copy the effects of more expensive illegal drugs,

such as methamphetamine and cocaine.

Synthetic cathinones (bath salts) are human-made drugs chemically similar to khât and are often stronger and more dangerous than

the natural product. They usually take the form of a white or brown

crystal-like powder, packaged in small plastic or foil bundles labeled

“not for human consumption,” or as “plant food,” “jewelry cleaner,”

or “phone screen cleaner,” and sold online and in drug paraphernalia

stores. The popular nickname Molly (slang for “molecular”) often

refers to the purported “pure” crystalline powder form of MDMA,

usually sold in capsules. However, people who purchase powder or

capsules sold as Molly often actually receive other drugs, such as synthetic cathinones. The uncertainty of what is actually in these synthetic

products, whose components might change from batch to batch, makes

them even more dangerous as anyone using them is unaware of what

the products contain and how their bodies will react.

The three most common synthetic cathinones are mephedrone,

methylone, and MDPV (3,4-methylenedioxypyrovalerone). With oral

ingestion, these drugs have an onset of action from 15–45 min, and

a duration that varies from 2–7 h. A recent study found that MDPV

affects the brain in a manner similar to cocaine but is at least 10 times

more potent. MDPV is the most common synthetic cathinone found

in the blood and urine of patients admitted to EDs after taking “bath

salts.” High doses, or chronic use, of synthetic cathinones can lead to

dangerous medical consequences, including psychosis, violent behaviors, tachycardia, hyperthermia, and even death.

The ability to synthesize addictive and dangerous drugs relatively

simply and rapidly, changing just a few molecules, yet retaining the

effects, has allowed many of these emerging drugs to outpace efforts to

regulate them, resulting in a developing global public health concern.

SUBSTANCE USE AND MENTAL HEALTH

According to the NSDUH, in 2019, among adults with no mental illness

16.6% consumed illicit drugs, compared to 49.4% with severe mental

illness and 38.8% with any mental illness. In 2019, among adults 18 years

of age or older, 61.2 million people had either mental illness or a substance use disorder in the past year, 42 million had mental illness in

the absence of a substance use disorder, 9.7 million had a substance use

disorder and no mental illness, and 9.5 million (3.8% of the population)

had both. Furthermore, based on 2018 NSDUH data it is estimated

that more than 1 in 10 adults (27.5 million) in the United States reported

ever having a substance use problem. Among those with a problem,

nearly 75% (20.5 million) reported being in recovery, which was associated with lower prevalence of past-year substance use and having

received substance use treatment. Self-reported prevalence of ever

having a substance use problem was 31.9% among adults with a lifetime

mental health problem but not in recovery, followed by 29.7% among

adults in recovery, compared with 7.0% among adults without a lifetime

mental health problem. Taken together, these data all point to the significant overlap of substance-related and other mental health problems.

GLOBAL CONSIDERATIONS

After nicotine, alcohol, and cannabis, stimulants are the next most

commonly used drugs globally, accounting for 68 million past-year

consumers. Past-year stimulant use worldwide for individuals aged

15–65 years approaches 29 million. Globally 7.4 million individuals

have a stimulant use disorder and it is thought that 11% of all people

who use stimulants develop such a disorder. The United Nations Office

on Drugs and Crime (UNODC) estimates that 1 in 7 people with substance use disorders receives treatment, and this number is thought

much lower in individuals with stimulant use disorder due to the lack

of pharmacologic treatments. Cocaine use globally had remained stable

until 2010 when it began to rise, driven by an increase in its use in

South America. Amphetamine use in Western Europe is still well below

5% lifetime prevalence for most countries, and methamphetamine

problems have been largely restricted to the Czech Republic; however, evidence indicates growing spread through Europe. Over threequarters of the world’s production of amphetamine-type stimulants

occurs in Southeast Asia and in recent years there has been a dramatic

increase in use in this region, particularly Thailand. In Japan and the

Philippines, methamphetamine use predominates. Lifetime experience

with ecstasy among the general population is still well below 5% in most

European countries, which is slightly lower than levels seen in Australia

(6%). Ecstasy is more prevalent in the West; however, over the past

decade use has increasingly become evident in other regions, including

Africa, South and Central America, the Caribbean, and parts of Asia.

Globally, psychostimulant use has been associated with elevated mortality, increased incidence of HIV and hepatitis C infection, poor mental

health (suicidality, psychosis, depression, and violence), and increased

risk of cardiovascular events. Globally, stigma and marginalization

make treatment of drug use disorders difficult and hinder sustainable

inclusive development incorporating gender and racial equity and the

empowerment of women and underrepresented minorities.

FUTURE DIRECTIONS

Despite their prevalence and public health impact, psychostimulant and

hallucinogen use disorders have no FDA-approved treatment medications. While behavioral therapies, such as contingency management

and CBT, have been shown effective in psychostimulant use disorders,

further research needs to be done regarding their utility for hallucinogen use disorders. Furthermore, based upon experience with opioid and

alcohol use disorders, it is likely that the most efficacious treatments will

employ a combination of behavioral and pharmacologic therapy.

Additionally, new approaches that utilize emerging technologies

have considerable potential for future treatment of psychostimulant use disorders. These include neurostimulation/neuromodulation

(TMS, TBS, tDCS), wearable biosensors, and mobile technology,

including ecologic and geographic momentary assessment (EMA/

GMA) as well as real-time interventions delivered via smartphone or

other mobile devices.

Acknowledgment

The authors would like to acknowledge the contributions of Dr. Antonello

Bonci to this chapter in previous editions.

3578 PART 13 Neurologic Disorders

■ FURTHER READING

Compton WM: Polysubstance use in the U.S. Opioid Crisis. Mol Psychiatry 26:41, 2021.

Farrell M et al: Responding to global stimulant use: challenges and

opportunities. Lancet 394:1652, 2019.

Trivedi MH et al: Bupropion and naltrexone in methamphetamine use

disorder. N Engl J Med 384:140, 2021.

Volkow ND et al: Neurobiologic advances from the brain disease

model of addiction. N Engl J Med 374:363, 2016.

■ WEBSITES

American Society of Addiction Medicine: https://www.asam.org/

public-resources

National Institute on Drug Abuse: https://www.drugabuse.gov/

drugs-abuse

World Health Organization: http://www.who.int/substance_abuse/en/

Poisoning, Drug Overdose, and Envenomation PART 14

Heavy Metal Poisoning

Howard Hu

458

Toxic metals (hereafter referred to simply as “metals”) pose a significant

threat to health through low-level as well as high level environmental

and occupational exposures. One indication of their importance relative to other potential hazards is their ranking by the U.S. Agency for

Toxic Substances and Disease Registry, which maintains an updated

list of all hazards present in toxic waste sites according to their prevalence and the severity of their toxicity. The first, second, third, and

seventh hazards on the list are heavy metals: arsenic, lead, mercury,

and cadmium, respectively (http://www.atsdr.cdc.gov/spl/). Specific

information pertaining to each of these four metals, including sources

and metabolism, toxic effects produced, diagnosis, and the appropriate

treatment for poisoning, is summarized in Table 458-1.

Metals are inhaled primarily as dusts and fumes (the latter defined

as tiny particles generated by combustion). Metal poisoning can also

result from exposure to vapors (e.g., mercury vapor in creating dental

amalgams). When metals are ingested in contaminated food or drink

or by hand-to-mouth activity (implicated especially in children), their

gastrointestinal absorption varies greatly with the specific chemical

form of the metal and the nutritional status of the host. Once a metal is

absorbed, blood is the main medium for its transport, with the precise

kinetics dependent on diffusibility, protein binding, rates of biotransformation, availability of intracellular ligands, and other factors. Some

organs (e.g., bone, liver, and kidney) sequester metals in relatively high

concentrations for years. Most metals are excreted through renal clearance and gastrointestinal excretion; some proportion is also excreted

through salivation, perspiration, exhalation, lactation, skin exfoliation,

and loss of hair and nails. The intrinsic stability of metals facilitates

tracing and measurement in biologic material, although the clinical

significance of the levels measured is not always clear.

Some metals, such as copper and selenium, are essential to normal

metabolic function as trace elements (Chap. 333) but are toxic at high

levels of exposure. Others, such as lead and mercury, are xenobiotic

and theoretically are capable of exerting toxic effects at any level of

exposure. Indeed, much research is currently focused on the contribution of low-level xenobiotic metal exposure to chronic diseases and

to subtle changes in health that may have significant public health

consequences. Genetic factors, such as polymorphisms that encode

for variant enzymes with altered properties in terms of metal binding,

transport, and effects, also may modify the impact of metals on health

and thereby account, at least in part, for individual susceptibility to

metal effects.

The most important component of treatment for metal toxicity is

the termination of exposure. Chelating agents are used to bind metals

into stable cyclic compounds with relatively low toxicity and to enhance

their excretion. The principal chelating agents are dimercaprol (British

anti-Lewisite [BAL]), ethylenediamine tetraacetic acid (EDTA), succimer (dimercaptosuccinic acid [DMSA]), and penicillamine; their

specific use depends on the metal involved and the clinical circumstances. Activated charcoal does not bind metals and thus is of limited

usefulness in cases of acute metal ingestion.

In addition to the information provided in Table 458-1, several other

aspects of exposure, toxicity, or management are worthy of discussion

with respect to the four most hazardous toxicants (arsenic, cadmium,

lead, and mercury).

Arsenic, even at moderate levels of exposure, has been clearly linked

with increased risks for cancer of the skin, bladder, renal pelvis, ureter,

kidney, liver, and lung. These risks appear to be modified by smoking,

folate and selenium status, genetic traits (such as ability to methylate arsenic), and other factors. Recent studies in community-based

populations have generated strong evidence that arsenic exposure is

also a risk factor for increased risk of hypertension, coronary heart

disease and stroke, lung function impairment, acute respiratory tract

infections, respiratory symptoms, and nonmalignant lung disease

mortality. The association with cardiovascular disease may hold at

levels of exposure in drinking water that are below the World Health

Organization (WHO) provisional guideline value of 10 μg/L. Evidence

has also continued to build indicating that low-level arsenic is a likely

cause of neurodevelopmental delays in children and likely contributes

to the development of diabetes.

Serious cadmium poisoning from the contamination of food and

water by mining effluents in Japan contributed to the 1946 outbreak

of “itai-itai” (“ouch-ouch”) disease, so named because of cadmiuminduced bone toxicity that led to painful bone fractures. Modest exposures from environmental contamination have been associated in some

studies with a lower bone density, a higher incidence of fractures, and

a faster decline in height in both men and women, effects that may be

related to cadmium’s calciuric and other toxic effects on the kidney.

Cadmium burdens have also been associated with an increased risk

of long-term kidney graft failure, and there is evidence for synergy

between the adverse impacts of cadmium and lead on kidney function.

Environmental exposures have also been linked to lower lung function

(even after adjusting for smoking cigarettes, which contain cadmium)

as well as increased risk of cardiovascular disease and mortality, stroke,

and heart failure. Cadmium triggers pulmonary inflammation, and a

recent population-based study of U.S. adults found that higher cadmium burdens are associated with higher mortality from influenza

or pneumonia. The International Agency for Research on Cancer has

classified cadmium as a known carcinogen, with evidence indicating it

contributes to elevated risks of prostate, lung, breast, and endometrial

cancer. Overall, this growing body of research indicates that cadmium

exposure is contributing significantly to morbidity and mortality rates

in the general population.

Advances in our understanding of lead toxicity have recently benefited by the development of K x-ray fluorescence (KXRF) instruments

for making safe in vivo measurements of lead levels in bone, which,

in turn, reflect cumulative exposure over many years, as opposed

to blood lead levels, which mostly reflect recent exposure. Higher

levels of cumulative lead exposure are now known to be a risk factor

for chronic disease, even though blood lead levels have continued to

decline in the general population over the past few decades following

the removal of lead from gasoline, plumbing, solder in food cans, and

other consumer products, with mean levels in the U.S. population now

hovering in the 1–2 μg/dL range. For example, higher bone lead levels

measured by KXRF have been linked to increased risk of hypertension

and accelerated declines in cognition in both men and women living

in urban communities. These relationships, in conjunction with other

epidemiologic and toxicologic studies, persuaded a federal expert panel

to conclude they were causal. Prospective studies have also demonstrated that higher bone lead levels, as well as blood lead levels as low

as 1–7 μg/dL, are a major risk factor for increased cardiovascular morbidity and mortality rates in both community-based and occupationalexposed populations. Lead exposure at community levels has also been

associated with increased risks of hearing loss, Parkinson’s disease, and

amyotrophic lateral sclerosis. With respect to pregnancy-associated

risks, high maternal bone lead levels were found to predict lower birth

weight, head circumference, birth length, and neurodevelopmental

performance in offspring by age 2 years. Offspring have also been

shown to have higher blood pressures at age 7–14 years, an age range at

which higher blood pressures are known to predict an elevated risk of

developing hypertension. In a randomized trial, calcium supplementation (1200 mg daily) was found to significantly reduce the mobilization

of lead from maternal bone into blood during pregnancy.

The toxicity of low-level organic mercury exposure (as manifested by neurobehavioral performance) is of increasing concern

3580 PART 14 Poisoning, Drug Overdose, and Envenomation

TABLE 458-1 Heavy Metals

MAIN SOURCES METABOLISM TOXICITY DIAGNOSIS TREATMENT

Arsenic

Smelting and

microelectronics

industries; wood

preservatives,

pesticides, herbicides,

fungicides; contaminant

of deep-water wells;

folk remedies; and coal;

incineration of these

products.

Organic arsenic

(arsenobetaine, arsenocholine)

is ingested in seafood and

fish, but is nontoxic; inorganic

arsenic is readily absorbed

(lung and GI); sequesters in

liver, spleen, kidneys, lungs, and

GI tract; residues persist in skin,

hair, and nails; biomethylation

results in detoxification, but this

process saturates.

Acute arsenic poisoning results

in necrosis of intestinal mucosa

with hemorrhagic gastroenteritis,

fluid loss, hypotension, delayed

cardiomyopathy, acute tubular

necrosis, and hemolysis.

Chronic arsenic exposure causes

diabetes, vasospasm, peripheral

vascular insufficiency and

gangrene, peripheral neuropathy,

and cancer of skin, lung, liver

(angiosarcoma), bladder, and

kidney.

Lethal dose: 120–200 mg (adults);

2 mg/kg (children).

Nausea, vomiting, diarrhea,

abdominal pain, delirium, coma,

seizures; garlicky odor on breath;

hyperkeratosis, hyperpigmentation,

exfoliative dermatitis, and Mees’

lines (transverse white striae of

the fingernails); sensory and motor

polyneuritis, distal weakness.

Radiopaque sign on abdominal

x-ray; ECG–QRS broadening, QT

prolongation, ST depression, T-wave

flattening; 24-h urinary arsenic

>67 μmol/d or 50 μg/d; (no seafood

× 24 h); if recent exposure, serum

arsenic >0.9 μmol/L (7 μg/dL). High

arsenic in hair or nails.

If acute ingestion, ipecac to

induce vomiting, gastric lavage,

activated charcoal with a

cathartic. Supportive care in

ICU.

Dimercaprol 3–5 mg/kg IM

q4h × 2 days; q6h × 1 day, then

q12h × 10 days; alternative: oral

succimer.

Cadmium

Metal plating, pigment,

smelting, battery, and

plastics industries;

tobacco; incineration

of these products;

ingestion of food that

concentrates cadmium

(grains, cereals, organ

meats).

Absorbed through ingestion

or inhalation; bound by

metallothionein, filtered at the

glomerulus, but reabsorbed

by proximal tubules (thus,

poorly excreted). Biologic

half-life: 10–30 y. Binds cellular

sulfhydryl groups, competes

with zinc, calcium for binding

sites. Concentrates in liver and

kidneys.

Acute cadmium inhalation causes

pneumonitis after 4–24 h; acute

ingestion causes gastroenteritis.

Chronic exposure causes

anosmia, yellowing of

teeth, emphysema, minor

LFT elevations, microcytic

hypochromic anemia

unresponsive to iron therapy,

proteinuria, increased urinary

β2

-microglobulin, calciuria,

leading to chronic renal failure,

osteomalacia, and fractures.

Possible risks of cardiovascular

disease and cancer.

With inhalation: pleuritic

chest pain, dyspnea, cyanosis,

fever, tachycardia, nausea,

noncardiogenic pulmonary edema.

With ingestion: nausea, vomiting,

cramps, diarrhea. Bone pain,

fractures with osteomalacia. If

recent exposure, serum cadmium

>500 nmol/L (5 μg/dL). Urinary

cadmium >100 nmol/L (10 μg/g

creatinine) and/or urinary β2

-

microglobulin >750 μg/g creatinine

(but urinary β2

-microglobulin also

increased in other renal diseases

such as pyelonephritis).

There is no effective treatment

for cadmium poisoning

(chelation not useful;

dimercaprol can exacerbate

nephrotoxicity).

Avoidance of further exposure,

supportive therapy, vitamin D

for osteomalacia.

Lead

Manufacturing of auto

batteries, lead crystal,

ceramics, fishing

weights, etc.; demolition

or sanding of leadpainted houses, bridges;

stained glass making,

plumbing, soldering;

environmental exposure

to paint chips, house

dust (in homes built

<1975), firing ranges

(from bullet dust), food

or water from improperly

glazed ceramics, lead

pipes; contaminated

herbal remedies,

candies; exposure to the

combustion of leaded

fuels.

Absorbed through ingestion

or inhalation; organic lead

(e.g., tetraethyl lead) absorbed

dermally. In blood, 95–99%

sequestered in RBCs—thus,

must measure lead in whole

blood (not serum). Distributed

widely in soft tissue, with

half-life ~30 days; 15% of

dose sequestered in bone

with half-life of >20 years.

Excreted mostly in urine,

but also appears in other

fluids including breast milk.

Interferes with mitochondrial

oxidative phosphorylation,

ATPases, calcium-dependent

messengers; enhances

oxidation and cell apoptosis.

Acute exposure with blood lead

levels (BPb) of >60–80 μg/dL

can cause impaired

neurotransmission and neuronal

cell death (with central and

peripheral nervous system

effects); impaired hematopoiesis

and renal tubular dysfunction.

At higher levels of exposure

(e.g., BPb >80–120 μg/dL),

acute encephalopathy with

convulsions, coma, and death

may occur. Subclinical exposures

in children (BPb 25–60 μg/dL)

are associated with anemia;

mental retardation; and deficits

in language, motor function,

balance, hearing, behavior, and

school performance. Impairment

of IQ appears to occur at even

lower levels of exposure with no

measurable threshold above the

limit of detection in most assays

of 1 μg/dL.

In adults, chronic subclinical

exposures (BPb >40 μg/dL) are

associated with an increased

risk of anemia, demyelinating

peripheral neuropathy (mainly

motor), impairments of reaction

time and hearing, accelerated

declines in cognition,

hypertension, ECG conduction

delays, hypertension, higher risk

of cardiovascular disease and

death, interstitial nephritis and

chronic renal failure, diminished

sperm counts, and spontaneous

abortions.

Abdominal pain, irritability, lethargy,

anorexia, anemia, Fanconi’s

syndrome, pyuria, azotemia in

children with blood lead level

(BPb) >80 μg/dL; may also see

epiphyseal plate “lead lines” on

long bone x-rays. Convulsions,

coma at BPb >120 μg/dL. Noticeable

neurodevelopmental delays at BPb of

40–80 μg/dL; may also see symptoms

associated with higher BPb levels.

Screening of all U.S. children when

they begin to crawl (~6 months) is

recommended by the CDC; source

identification and intervention is

begun if the BPb >10 μg/dL. In adults,

acute exposure causes similar

symptoms as in children as well as

headaches, arthralgias, myalgias,

depression, impaired short-term

memory, loss of libido. Physical

examination may reveal a “lead line”

at the gingiva-tooth border, pallor,

wrist drop, and cognitive dysfunction

(e.g., declines on the mini-mental

state exam); lab tests may reveal a

normocytic, normochromic anemia,

basophilic stippling, an elevated

blood protoporphyrin level (free

erythrocyte or zinc), and motor delays

on nerve conduction. U.S. OSHA

requires regular testing of leadexposed workers with removal if BPb

>40 μg/dL. Newer guidelines have

been proposed recommending that

BPb be maintained at <10 μg/dL,

removal of workers if BPb >20 μg/dL,

and monitoring of cumulative

exposure parameters.

Identification and correction

of exposure sources is critical.

In some U.S. states, screening

and reporting to local health

boards of children with BPb

>10 μg/dL and workers with

BPb >40 μg/dL are required. In

the highly exposed individual

with symptoms, chelation

is recommended with oral

DMSA (succimer); if acutely

toxic, hospitalization and

IV or IM chelation with

ethylenediaminetetraacetic

acid calcium disodium

(CaEDTA) may be required, with

the addition of dimercaprol

to prevent worsening of

encephalopathy. It is uncertain

whether children with

asymptomatic lead exposure

(e.g., BPb 20–40 μg/dL) benefit

from chelation; a recent

randomized trial showed no

benefit. Correction of dietary

deficiencies in iron, calcium,

magnesium, and zinc will lower

lead absorption and may also

improve toxicity. Vitamin C is

a weak but natural chelating

agent. Calcium supplements

(1200 mg at bedtime) have been

shown to lower blood lead

levels in pregnant women.

(Continued)

3581Heavy Metal Poisoning CHAPTER 458

TABLE 458-1 Heavy Metals

MAIN SOURCES METABOLISM TOXICITY DIAGNOSIS TREATMENT

Mercury

Metallic, mercurous,

and mercuric mercury

(Hg, Hg+

, Hg2+) exposures

occur in some chemical,

metal-processing,

electrical equipment,

automotive industries;

they are also in

thermometers, dental

amalgams, batteries.

Mercury is dispersed

by waste incineration.

Environmental bacteria

convert inorganic to

organic mercury, which

then bioconcentrates up

the aquatic food chain

to contaminate tuna,

swordfish, and other

pelagic fish.

Elemental mercury (Hg) is not

well absorbed; however, it will

volatilize into highly absorbable

vapor. Inorganic mercury is

absorbed through the gut and

skin. Organic mercury is well

absorbed through inhalation

and ingestion. Elemental

and organic mercury cross

the blood-brain barrier and

placenta. Mercury is excreted

in urine and feces and has a

half-life in blood of ~60 days;

however, deposits will remain

in the kidney and brain for

years. Exposure to mercury

stimulates the kidney to

produce metallothionein, which

provides some detoxification

benefit. Mercury binds

sulfhydryl groups and interferes

with a wide variety of critical

enzymatic processes.

Acute inhalation of Hg vapor

causes pneumonitis and

noncardiogenic pulmonary

edema leading to death, CNS

symptoms, and polyneuropathy.

Chronic high exposure causes

CNS toxicity (mercurial erethism;

see Diagnosis); lower exposures

impair renal function, motor

speed, memory, coordination.

Acute ingestion of inorganic

mercury causes gastroenteritis,

the nephritic syndrome, or acute

renal failure, hypertension,

tachycardia, and cardiovascular

collapse, with death at a dose of

10–42 mg/kg.

Ingestion of organic mercury

causes gastroenteritis,

arrhythmias, and lesions in the

basal ganglia, gray matter, and

cerebellum at doses >1.7 mg/kg.

High exposure during pregnancy

causes derangement of fetal

neuronal migration resulting in

severe mental retardation.

Mild exposures during pregnancy

(from fish consumption) are

associated with declines in

neurobehavioral performance in

offspring.

Dimethylmercury, a compound

only found in research labs, is

“supertoxic”—a few drops of

exposure via skin absorption or

inhaled vapor can cause severe

cerebellar degeneration and

death.

Chronic exposure to metallic

mercury vapor produces a

characteristic intention tremor and

mercurial erethism: excitability,

memory loss, insomnia, timidity, and

delirium (“mad as a hatter”). On

neurobehavioral tests: decreased

motor speed, visual scanning, verbal

and visual memory, visuomotor

coordination.

Children exposed to mercury in

any form may develop acrodynia

(“pink disease”): flushing, itching,

swelling, tachycardia, hypertension,

excessive salivation or perspiration,

irritability, weakness, morbilliform

rashes, desquamation of palms and

soles.

Toxicity from elemental or inorganic

mercury exposure begins when

blood levels >180 nmol/L (3.6 μg/dL)

and urine levels >0.7 μmol/L

(15 μg/dL). Exposures that ended

years ago may result in a >20-μg

increase in 24-h urine after a 2-g

dose of succimer.

Organic mercury exposure is best

measured by levels in blood (if

recent) or hair (if chronic); CNS

toxicity in children may derive from

fetal exposures associated with

maternal hair Hg >30 nmol/g (6 μg/g).

Treat acute ingestion of

mercuric salts with induced

emesis or gastric lavage

and polythiol resins (to bind

mercury in the GI tract). Chelate

with dimercaprol (up to

24 mg/kg per day IM in divided

doses), DMSA (succimer),

or penicillamine, with 5-day

courses separated by several

days of rest. If renal failure

occurs, treat with peritoneal

dialysis, hemodialysis, or

extracorporeal regional

complexing hemodialysis and

succimer.

Chronic inorganic mercury

poisoning is best treated with

N-acetyl penicillamine.

Abbreviations: ATPase, adenosine triphosphatase; BPb, blood lead; CDC, Centers for Disease Control and Prevention; CNS, central nervous system; DMSA,

dimercaptosuccinic acid; ECG, electrocardiogram; GI, gastrointestinal; ICU, intensive care unit; IQ, intelligence quotient; LFT, liver function tests; OSHA, Occupational Safety

and Health Administration; RBC, red blood cell.

(Continued)

based on studies of the offspring of mothers who ingested mercurycontaminated fish. With respect to whether the consumption of fish

by women during pregnancy is good or bad for offspring neurodevelopment, balancing the trade-offs of the beneficial effects of the

omega-3-fatty acids (FAs) in fish versus the adverse effects of mercury

contamination in fish has led to some confusion and inconsistency in

public health recommendations. Overall, it would appear that it would

be best for pregnant women to either limit fish consumption to those

species known to be low in mercury contamination but high in omega3-FAs (such as sardines or mackerel) or to avoid fish and obtain omega3-FAs through supplements or other dietary sources. Accumulated

evidence has not supported the contention that ethyl mercury, used as

a preservative in multiuse vaccines administered in early childhood,

has played a significant role in causing neurodevelopmental problems

such as autism. With regard to adults, there is conflicting evidence

as to whether mercury exposure is associated with increased risk of

hypertension and cardiovascular disease. There is also some evidence

that mercury exposure in the general population is associated with the

development of diabetes, perturbations in markers of autoimmunity,

and depression. At this point, conclusions cannot be drawn and the

clinical significance of these findings remains unclear.

Heavy metals pose risks to health that are especially burdensome

in selected parts of the world. For example, arsenic exposure from

natural contamination of shallow tube wells inserted for drinking

water is a major environmental problem for millions of residents in

parts of Bangladesh and Western India. Contamination was formerly

considered only a problem with deep wells; however, the geology of this

region allows most residents only a few alternatives for potable drinking water. Arsenic contamination of drinking water is also a major

problem in China, Argentina, Chile, Mexico, and some regions of the

United States (Maine, New Hampshire, Massachusetts). The global

campaign to phase out leaded gasoline has had continued success, with

only a few countries still remaining (Algeria, Iraq, Yemen, Myanmar,

North Korea, and Afghanistan). However, significant population exposures to lead remain, particularly in the United States with respect to

older housing that contains lead paint or that receives drinking water

through lead pipes, and there are indications that exposures are beginning to increase again in many low- and middle-income countries due

to industrial pollution, electronic waste, and a variety of contaminated

consumer products. Populations living in the Arctic have been shown

to have particularly high exposures to mercury due to long-range transport patterns that concentrate mercury in the polar regions, as well as

the traditional dependence of Arctic peoples on the consumption of

fish and other wildlife that bioconcentrate methylmercury.

A few additional metals deserve brief mention but are not covered

in Table 458-1 because of the relative rarity of their being clinically

encountered or the uncertainty regarding their potential toxicities.

Aluminum contributes to the encephalopathy in patients with severe

renal disease, who are undergoing dialysis (Chap. 410). High levels

of aluminum are found in the neurofibrillary tangles in the cerebral

3582 PART 14 Poisoning, Drug Overdose, and Envenomation

cortex and hippocampus of patients with Alzheimer’s disease, as well

as in the drinking water and soil of areas with an unusually high incidence of Alzheimer’s. The experimental and epidemiologic evidence

for the aluminum–Alzheimer’s disease link remains relatively weak,

however, and it cannot be concluded that aluminum is a causal agent

or a contributing factor in neurodegenerative disease. Hexavalent

chromium is corrosive and sensitizing. Workers in the chromate and

chrome pigment production industries have consistently had a greater

risk of lung cancer. The introduction of cobalt chloride as a fortifier in

beer led to outbreaks of fatal cardiomyopathy among heavy consumers.

Occupational exposure (e.g., of miners, dry-battery manufacturers,

and arc welders) to manganese (Mn) can cause a parkinsonian syndrome within 1–2 years, including gait disorders; postural instability; a

masked, expressionless face; tremor; and psychiatric symptoms. With

the introduction of methylcyclopentadienyl manganese tricarbonyl

(MMT) as a gasoline additive, there is concern for the toxic potential

of environmental manganese exposure. Some epidemiologic studies

have found an association between the prevalence of parkinsonian disorders and estimated manganese exposures emitted by local ferroalloy

industries; others have found evidence suggesting that manganese may

interfere with early childhood neurodevelopment in ways similar to

that of lead. Manganese toxicity is clearly associated with dopaminergic dysfunction, and its toxicity is likely influenced by age, gender,

ethnicity, genetics, and preexisting medical conditions. Nickel exposure

induces an allergic response, and inhalation of nickel compounds with

low aqueous solubility (e.g., nickel subsulfide and nickel oxide) in

occupational settings is associated with an increased risk of lung cancer. Overexposure to selenium may cause local irritation of the respiratory system and eyes, gastrointestinal irritation, liver inflammation,

loss of hair, depigmentation, and peripheral nerve damage. Workers

exposed to certain organic forms of tin (particularly trimethyl and triethyl derivatives) have developed psychomotor disturbances, including

tremor, convulsions, hallucinations, and psychotic behavior.

Thallium, which is a component of some insecticides, metal alloys,

and fireworks, is absorbed through the skin as well as by ingestion and

inhalation. Severe poisoning follows a single ingested dose of >1 g or

>8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis

precede confusion, psychosis, organic brain syndrome, and coma.

Thallium is radiopaque. Induced emesis or gastric lavage is indicated

within 4–6 h of acute ingestion; Prussian blue prevents absorption

and is given orally at 250 mg/kg in divided doses. Unlike other types

of metal poisoning, thallium poisoning may be less severe when activated charcoal is used to interrupt its enterohepatic circulation. Other

measures include forced diuresis, treatment with potassium chloride

(which promotes renal excretion of thallium), and peritoneal dialysis.

Chelation therapy remains the treatment of choice for most toxic

metals in the setting of severe acute clinical poisoning. However, the

use of chelation for treating chronic diseases remains controversial, in

part because of the lack of evidence from rigorous randomized clinical

trials. One area for which there is moderate evidence is the use of chelation in patients with higher than average levels of accumulated lead

burdens as a means of improving kidney function. The results from a

series of randomized trials conducted in Taiwan suggest that among

individuals with mildly elevated lead burdens (defined as between 150

and 600 μg of lead per 72-h urine upon an EDTA mobilization test

[1 g EDTA]), weekly calcium disodium EDTA chelation treatments for

between 2 and 27 months can improve renal function outcomes, both

in individuals with and without type 2 diabetes.

The Trial to Assess Chelation Therapy (TACT), a multicenter, doubleblind, placebo-controlled, prospective randomized trial funded by the

National Institutes of Health of 1708 patients aged ≥50 years who had

experienced a myocardial infarction (MI), found that a protocol of

repeated intravenous chelation with disodium EDTA, compared with

placebo, modestly but significantly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures.

The effect was particularly pronounced among those with concurrent

diabetes. However, the trial did not include rigorous measures of exposure to lead or other metals or any selection criteria based on metals

exposure; thus, even though chelation reduces metal burdens, which

have been associated with adverse cardiovascular effects (especially

lead), it remains unclear whether the beneficial effects result from a

reduction in metal burden. In view of the risks of side effects associated with chelation, by themselves, the results are not sufficient to

support the routine use of chelation therapy for treatment of patients

either who have had an MI or who have had low-level lead exposure.

A follow-up trial with rigorous measures of metals exposure is ongoing.

■ FURTHER READING

Alamolhodaei NS et al: Arsenic cardiotoxicity: An overview. Environ

Toxicol Pharmacol 40:1005, 2015.

Aneni EC et al: Chronic toxic metal exposure and cardiovascular

disease: Mechanisms of risk and emerging role of chelation therapy.

Curr Atheroscler Rep 18:81, 2016.

Gidlow DA: Lead toxicity. Occup Med (Lond) 65:348, 2015.

Kim KH et al: A review on the distribution of Hg in the environment

and its human health impacts. J Hazard Mater 306:376, 2016.

Lamas GA et al: Heavy metals, cardiovascular disease, and the unexpected benefits of chelation therapy. J Am Coll Cardiol 67:2411, 2016.

Lanphear BP et al: Low-level lead exposure and mortality in US

adults: A population-based cohort study. Lancet Public Health

3:e177, 2018.

O’Neal SL, Zheng W: Manganese toxicity upon overexposure:

A decade in review. Curr Environ Health Rep 2:315, 2015.

Park SK et al: Environmental cadmium and mortality from influenza

and pneumonia in U.S. adults. Environ Health Perspect 128:127004,

2020.

Tellez-Plaza M et al: Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. Environ Health

Perspect 120:1017, 2012.

Weaver VM et al: Does calcium disodium EDTA slow CKD progression? Am J Kidney Dis 60:503, 2012.

Xu L et al: Positive association of cardiovascular disease (CVD) with

chronic exposure to drinking water arsenic (As) at concentrations

below the WHO provisional guideline value: A systematic review and

meta-analysis. Int J Environ Res Public Health 17:2536, 2020.

Poisoning refers to the development of dose-related adverse effects

following exposure to chemicals, drugs, or other xenobiotics. To paraphrase Paracelsus, the dose makes the poison. Although most poisons

have predictable dose-related effects, individual responses to a given

dose may vary because of genetic polymorphism, enzymatic induction

or inhibition in the presence of other xenobiotics, or acquired tolerance. Poisoning may be local (e.g., skin, eyes, or lungs) or systemic

depending on the route of exposure, the chemical and physical properties of the poison, and its mechanism of action. The severity and

reversibility of poisoning also depend on the functional reserve of the

individual or target organ, which is influenced by age and preexisting

disease.

EPIDEMIOLOGY

More than 5 million poison exposures occur in the United States each

year. Most are acute, are accidental (unintentional), involve a single

agent, occur in the home (>90%), result in minor or no toxicity, and

involve children <6 years of age. Pharmaceuticals are involved in 47%

of poisoning exposures and in 84% of serious or fatal poisonings.

Household cleaning substances and cosmetics/personal care products

459 Poisoning and Drug

Overdose

Mark B. Mycyk

3583Poisoning and Drug Overdose CHAPTER 459

events. Patients need to be asked explicitly about their prescribed medications and recreational drug use. Drugs previously considered “illicit”

such as cannabinoids are now legal in many states and prescribed for

therapeutic purposes. A search of clothes, belongings, and place of discovery may reveal a suicide note or a container of drugs or chemicals.

Without a clear history in a patient clinically suspected to be poisoned,

all medications available anywhere in the patient’s home or belongings

should be considered as possible agents, including medications for

pets. Review of the patient’s record in the state prescription monitoring

program (PMP) may disclose relevant history of Schedule II, III, IV,

and V controlled substance use. The imprint code on pills and the

label on chemical products may be used to identify the ingredients and

potential toxicity of a suspected poison by consulting a reference text,

a computerized database, the manufacturer, or a regional poison information center (800-222-1222). Occupational exposures require review

of any available safety data sheet (SDS) from the worksite. Because

of increasing globalization from travel and internet consumerism,

unfamiliar poisonings may result in local emergency department evaluation. Pharmaceuticals, industrial chemicals, or drugs of abuse from

foreign countries may be identified with the assistance of a regional

poison center or via the World Wide Web.

■ PHYSICAL EXAMINATION AND CLINICAL COURSE

The physical examination should focus initially on vital signs, the cardiopulmonary system, and neurologic status. The neurologic examination should include documentation of neuromuscular abnormalities

such as dyskinesia, dystonia, fasciculations, myoclonus, rigidity, and

tremors. The patient should also be examined for evidence of trauma

and underlying illnesses. Focal neurologic findings are uncommon in

poisoning, and their presence should prompt evaluation for a structural central nervous system (CNS) lesion. Examination of the eyes (for

nystagmus and pupil size and reactivity), abdomen (for bowel activity

and bladder size), and skin (for burns, bullae, color, warmth, moisture,

pressure sores, and puncture marks) may reveal findings of diagnostic

value. When the history is unclear, all orifices should be examined for

the presence of chemical burns and drug packets. The odor of breath

or vomitus and the color of nails, skin, or urine may provide important

diagnostic clues.

The diagnosis of poisoning in cases of unknown etiology primarily

relies on pattern recognition. The first step is to assess the pulse, blood

pressure, respiratory rate, temperature, and neurologic status and to

characterize the overall physiologic state as stimulated, depressed,

discordant, or normal (Table 459-1). Obtaining a complete set of vital

signs and reassessing them frequently are critical. Measuring core

temperature is especially important, even in difficult or combative

patients, since temperature elevation is the most reliable prognosticator

of poor outcome in poisoning from stimulants (e.g., cocaine) or drug

withdrawal (e.g., alcohol or γ-hydroxybutyric acid [GHB]). The next

step is to consider the underlying causes of the physiologic state and

to attempt to identify a pathophysiologic pattern or toxic syndrome

(toxidrome) based on the observed findings. Assessing the severity of

physiologic derangements (Table 459-2) is useful in this regard and

also for monitoring the clinical course and response to treatment. In

cases of polydrug overdose involving different drug classes, identifying

a clear toxidrome can be challenging if the different drugs counteract

the physiologic effects of one another. The final step is to attempt

to identify the particular agent involved by looking for unique or

relatively poison-specific physical or ancillary test abnormalities. Distinguishing among toxidromes on the basis of the physiologic state is

summarized next.

The Stimulated Physiologic State Increased pulse, blood pressure,

respiratory rate, temperature, and neuromuscular activity characterize the

stimulated physiologic state, which can reflect sympathetic, anticholinergic, or hallucinogen poisoning or drug withdrawal (Table 459-1). Other

features are noted in Table 459-2. Mydriasis, a characteristic feature of

all stimulants, is most marked in anticholinergic poisoning since pupillary reactivity relies on muscarinic control. In sympathetic poisoning

(e.g., due to cocaine), pupils are also enlarged, but some reactivity to

are the most common nonpharmaceutical exposures reported to the

National Poison Data System (NPDS). In the last decade, the rate of

injury-related deaths from poisoning has overtaken the rate of deaths

related to motor-vehicle crashes in the United States. According to the

Centers for Disease Control and Prevention (CDC), twice as many

Americans died from drug overdoses in 2014 compared to 2000.

Although prescription opioids have appropriately received attention as

a major reason for the increased number of poisoning deaths, the availability of other pharmaceuticals and rapid proliferation of novel drugs

of abuse also contribute to the increasing death rate. In many parts of

the United States, where these issues are particularly prevalent, there

are efforts to develop better prescription drug databases and enhanced

training for health care professionals in pain management and the use

of opioids. Unintentional exposures can result from the improper use

of chemicals at work or play; label misreading; product mislabeling;

mistaken identification of unlabeled chemicals; uninformed selfmedication; and dosing errors by nurses, pharmacists, physicians,

parents, and the elderly. Excluding the recreational use of ethanol,

attempted suicide (deliberate self-harm) is the most common reported

reason for intentional poisoning. Recreational use of prescribed and

over-the-counter drugs for psychotropic or euphoric effects (abuse) or

excessive self-dosing (misuse) is increasingly common and may also

result in unintentional self-poisoning.

About 20–25% of exposures require bedside health-professional

evaluation, and 5% of all exposures require hospitalization. Poisonings

account for 5–10% of all ambulance transports, emergency department visits, and intensive care unit admissions. Hospital admissions

related to poisoning are also associated with longer lengths of stay and

increase the utilization of resources such as radiography and other

laboratory services. Up to 35% of psychiatric admissions are prompted

by attempted suicide via overdosage with cases involving adolescents

steadily increasing during the last decade. Overall, the mortality rate is

low: <1% of all poisoning exposures. It is significantly higher (1–2%)

among hospitalized patients with intentional (suicidal) overdose or

complications from drugs of abuse, who account for the majority of

serious poisonings. Acetaminophen is the pharmaceutical agent most

often implicated in fatal poisoning. Overall, carbon monoxide is the

leading cause of death from poisoning, but this prominence is not

reflected in hospital or poison center statistics because patients with

such poisoning are typically dead when discovered and are referred

directly to medical examiners.

DIAGNOSIS

Although poisoning can mimic other illnesses, the correct diagnosis

can usually be established by the history, physical examination, routine and toxicologic laboratory evaluations, and characteristic clinical

course.

■ HISTORY

The history should include the time, route, duration, and circumstances (location, surrounding events, and intent) of exposure; the

name and amount of each drug, chemical, or ingredient involved; the

time of onset, nature, and severity of symptoms; the time and type of

first-aid measures provided; the medical and psychiatric history; and

occupation.

In many cases, the patient is confused, comatose, unaware of an

exposure, or unable or unwilling to admit to one. Suspicious circumstances include unexplained sudden illness in a previously healthy

person or a group of healthy people; a history of psychiatric problems

(particularly depression or bipolar disorder); recent changes in health,

economic status, or social relationships; and onset of illness during

work with chemicals or after ingestion of food, drink (especially ethanol), or medications. When patients become ill soon after arriving

from a foreign country or being arrested for criminal activity, “body

packing” or “body stuffing” (ingesting or concealing illicit drugs in a

body cavity) should be suspected. Relevant information may be available from family, friends, paramedics, police, pharmacists, physicians,

and employers, who should be questioned regarding the patient’s habits, hobbies, behavioral changes, available medications, and antecedent