3566 PART 13 Neurologic Disorders

six decades that caused the dramatic rise in rates of adenocarcinoma

of the lung observed over the past half century. There has been no

increase in risk of lung cancer or adenocarcinoma of the lung over the

same period among never smokers.

CESSATION

The process of stopping smoking is commonly a cyclical one, with the

smoker sometimes making multiple attempts to quit and failing before

finally being successful. Approximately 70–80% of smokers would like

to quit smoking. More than one-half of current smokers attempted to

quit in the last year, but only 6% quit for 6 months, and only 3% remain

abstinent for 2 years. Clinician-based smoking interventions should

repeatedly encourage smokers to try to quit and to use different forms

of cessation assistance with each new cessation attempt, rather than

focusing exclusively on immediate cessation at the time of the first visit.

Advice from a physician to quit smoking, particularly at the time of

an acute illness, is a powerful trigger for cessation attempts, with up

to half of patients who are advised to quit making a cessation effort.

Other triggers that may be enhanced by timely physician advice to

quit include increases in the tax on cigarettes, media campaigns, and

changes in rules to restrict smoking in the workplace.

PHYSICIAN INTERVENTION (TABLE 454-3)

All patients should be asked whether they smoke, how much they

smoke, how long they have smoked, their past experience with quitting, and whether they are currently interested in quitting. The number

of cigarettes smoked per day and smoking within 30 min of waking are

useful measures of the intensity of nicotine addiction. Even those who

are not interested in quitting should be encouraged and motivated to

quit; provided a clear, strong, and personalized message by the clinician

that smoking is an important health concern; and offered assistance

if they become interested in quitting in the future. Many of those not

currently expressing an interest in quitting may nevertheless make an

attempt to quit in the subsequent year. For those interested in quitting, a quit date should be negotiated, usually not the day of the visit

but within the next few weeks, and a follow-up contact by office staff

around the time of the quit date should be provided. There is a relationship between the amount of assistance a patient is willing to accept

and the success of the cessation attempt.

There are a variety of nicotine-replacement products, including

over-the-counter nicotine patches, gum, and lozenges, as well as nicotine nasal and oral inhalers available by prescription. These products

can be used for up to 3–6 months, and some products are formulated

to allow a gradual step-down in dosage with increasing duration of

smoking abstinence. Antidepressants such as bupropion (300 mg in

divided doses for up to 6 months) have also been shown to be effective, as has varenicline, a partial agonist for the nicotinic acetylcholine

receptor (initial dose 0.5 mg daily increasing to 1 mg twice daily at

day 8; treatment duration up to 6 months). Combined use of nicotinereplacement therapy (NRT) and antidepressants as well as the use

of gum or lozenges for acute cravings in patients using patches can

increase cessation outcomes. Pretreatment with antidepressants or

varenicline is recommended for 1–2 weeks prior to the quit date.

Pretreatment with nicotine-replacement products is also useful prior

to a cessation date. Longer duration of nicotine replacement as a

maintenance therapy for those who are unsuccessful in quitting with a

shorter duration of use is a useful strategy. NRT is provided in different dosages, with higher doses being recommended for more intense

smokers. Clonidine or the tricyclic antidepressant nortriptyline should

be reserved for patients who have failed on first-line pharmacologic

treatment or who are unable to use other therapies. Antidepressants are

more effective among smokers with a history of depression symptoms.

Current recommendations are to offer pharmacologic treatment,

usually with nicotine patches or varenicline, to all who will accept it

and to provide counseling and other support as a part of the cessation attempt. Cessation advice alone by a physician or his or her staff

is likely to increase success compared with no intervention; a more

comprehensive approach with advice, pharmacologic assistance, and

counseling can increase cessation success nearly threefold.

For adult addicted smokers, switching to exclusive use of e-cigarettes,

but not dual use with combusted cigarettes, can promote combusted

cigarette cessation, particularly for those unlikely to try to quit with

other proven cessation modalities.

Incorporation of cessation assistance into a practice requires a

change of the care delivery infrastructure. Simple changes include

(1) adding questions about smoking and interest in cessation on

patient-intake questionnaires, (2) asking patients whether they smoke

as part of the initial vital sign measurements made by office staff, (3)

listing smoking as a problem in the medical record, and (4) automating

follow-up contact with the patient on the quit date. These changes are

essential to institutionalizing smoking intervention within the practice

setting; without this institutionalization, the best intentions of physicians to intervene with their patients who smoke are often lost in the

time crush of a busy practice.

PREVENTION

Approximately 85% of individuals who become cigarette smokers

initiate the behavior during adolescence. Factors that promote adolescent initiation are parental or older-sibling cigarette smoking, tobacco

advertising and promotional activities, the availability of cigarettes, and

the social acceptability of smoking. The need for an enhanced self-image

and to imitate adult behavior is greatest for those adolescents who have

the least external validation of their self-worth, which may explain in

part the enormous differences in adolescent smoking prevalence by

socioeconomic and school performance strata.

Prevention of smoking initiation must begin early, preferably in the

elementary school years. Physicians who treat adolescents should be

sensitive to the prevalence of this problem even in the preteen population. Physicians should ask all adolescents whether they have experimented with nicotine or currently use nicotine products, reinforce the

fact that most adolescents and adults do not smoke or use nicotine, and

explain that all forms of nicotine intake are both addictive and harmful.

TABLE 454-3 Clinical Practice Guidelines

Physician Actions

Ask: Systematically identify all tobacco users at every visit

Advise: Strongly urge all smokers to quit

Identify smokers willing to quit

Assist the patient in quitting

Arrange follow-up contact

Effective Pharmacologic Interventionsa

First-line therapies

Nicotine gum (1.5)

Nicotine patch (1.9)

Nicotine nasal inhaler (2.3)

Nicotine oral inhaler (2.1)

Nicotine lozenge (2 mg: 2.0, 4 mg: 2.8)

Bupropion (2.0)

Varenicline (3.1)

Second-line therapies

Clonidine (2.1)

Nortriptyline (1.8)

Other Effective Interventionsa

Physician or other medical personnel counseling (10 min) (1.84)

Intensive group smoking cessation programs (at least 4–7 sessions of 20- to

30-min duration lasting at least 2 and preferably 8 weeks) (1.3)

Intensive individual counseling (1.7)

Clinic-based smoking status identification system (3.1)

Telephone counseling (1.6)

Exclusive E-cigarette use (3.0)

a

Numerical value following the intervention is the multiple for cessation success

compared to no intervention.

3567 Marijuana and Marijuana Use Disorders CHAPTER 455

Marijuana is the most widely used illicit drug, with ~192 million

users worldwide and with >43 million Americans having used it in

2018. Cannabis strains fall into those grown for their euphorigenic

and medical properties (i.e., for their Δ-9-tetrahydrocannabinol

[THC] content), and “hemp,” which is grown for seed, fiber, and

cannabidiol (CBD). As of August 2020, Canada and 43 U.S. states

have decriminalized and/or “medicalized” marijuana or marijuanaderived products, which has increased the availability of cannabis

strains and derived products. Between 2008 and 2017, the average

THC content in marijuana increased from 8.9% to 17.1%. Today,

THC concentrations in marijuana flowers found in dispensaries can

exceed 25%, while oil extracts used for “vaping” can contain >95%

THC. Similar high THC concentrations are found in solid cannabis

concentrates (e.g., wax or shatter) used for “dabbing,” which involves

vaporization with a propane torch. Vaping and dabbing both provide

very high THC levels with a rapid absorption and speed of effect

onset, a phenomenon that increases addiction risk. Cannabis-infused

“edibles” (e.g., gummy bears, cookies, chocolates, and drinks) are

also widely available and valued for their discreet administration and

perception of reduced harm.

■ PHARMACOLOGIC EFFECTS

Cannabis is used recreationally because it enhances the subjective

sense of well-being, provides rewarding sensations, and can decrease

stress responses. However, consumption of high THC doses can induce

anxiety, paranoia, and panic. THC is primarily an agonist (activator)

of G protein–coupled cannabinoid receptors (CB1R and CB2R), with

the euphoric effects mediated through CB1Rs located on excitatory

glutamatergic and inhibitory γ-aminobutyric acid (GABA)-ergic interneurons and glial cells in brain regions that process stress, mood,

and reward. These receptors are the effectors of the endocannabinoid

system (ECS), which is physiologically activated by 2-arachidonoylglycerol (2-AG, a full agonist) and anandamide (a partial agonist). According to current understanding, 2-AG modulates synaptic

455 Marijuana and Marijuana

Use Disorders

Nora D. Volkow, Aidan Hampson, Ruben Baler

■ FURTHER READING

Eisenberg MJ et al: Effect of e-cigarettes plus counseling vs counseling alone on smoking cessation: A randomized clinical trial. JAMA

324:1844, 2020.

Hajek P et al: A randomized trial of e-cigarettes versus nicotinereplacement therapy. N Engl J Med 380:629, 2019.

Leone FT et al: Initiating pharmacologic treatment in tobaccodependent adults. An official American Thoracic Society Clinical

Practice Guideline. Am J Respir Crit Care Med 202:e5, 2020.

Sohn HS et al: Evidence supporting the need for considering the

effects of smoking on drug disposition and effectiveness in medication practices: A systematic narrative review. Int J Clin Pharmacol

Ther 53:621, 2015.

U.S. Department of Health and Human Services: U.S. Department

of Health and Human Services. Smoking Cessation. A Report of the

Surgeon General. Atlanta, GA, 2020. Available from https://www.

hhs.gov/sites/default/files/2020-cessation-sgr-full-report.pdf. Accessed

May 2, 2020.

U.S. Department of Health and Human Services: The Health

Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon

General. Atlanta, GA, 2014. Available from https://www.ncbi.nlm.

nih.gov/books/NBK179276/pdf/Bookshelf_NBK179276.pdf. Accessed

May 2, 2020.

signaling by inhibiting overstimulated synapses. Endocannabinoids are

synthesized and eliminated on demand and thus provide a temporally

and regionally specific control signal. In contrast, the effect of THC is

not defined by synaptic necessity but by the dose taken and pharmacokinetics, and so it disrupts ECS neuroregulation. THC is a partial

CB1/2R agonist (it produces less signal per receptor bound) and thus

does not inhibit glutamate release as effectively as 2-AG but can outcompete endocannabinoids by mass action. However, GABA-releasing

interneurons have more CB1R than they have connecting intracellular

signaling components, and so THC and 2-AG inhibit GABA release to

a similar degree. This may explain the subjective similarity of THC and

GABA inhibitors such as benzodiazepines.

The rewarding effects of THC are thought to be mediated by

modulation of glutamatergic and GABAergic activity in the ventral

tegmental area in the midbrain, the nucleus that contains the dopaminergic neurons projecting into the nucleus accumbens, which integrates

glutamate and dopamine signals to produce reward responses. The

anxiety-reducing effects of THC are mediated by its effects in the amygdala, a region critical for threat perception and emotional reactivity.

■ CANNABIS PHARMACOKINETICS

Traditional smoking (e.g., joints and water pipes) is the main route of

administration, but the rise of e-cigarette–derived vaping concentrates

(vape pens) has led to a move to small dosing and more regular administration, also known as micro-dosing. Vape pens use concentrate

liquids and offer both an easier dose control mechanism and more

discreet consumption. The subjective effects of marijuana are affected

by dose, route of administration, (smoked, vaped, ingested), and the

subject’s prior experience. Smoked THC exhibits a bioavailability of

10–35%, with interindividual differences stemming from individual

variations in the capacity to hold smoke in the lungs long enough

for maximal absorption. The pharmacokinetics (PKs) of heated (not

burnt) marijuana is similar to that of the smoked flower, but no data

are available to address the PKs of oils and solid concentrates. When

smoked, THC is rapidly absorbed (Tmax within 5–10 min) and displays

three phases of elimination. After Tmax, plasma levels drop rapidly

(alpha half-life [t1/2] ~6 min) due to redistribution from plasma to

lipophilic tissues such as adipose and brain. As a result, the brain continues to accumulate THC while plasma levels decline, so subjective

effects max out at ~20–30 min. This “hysteresis” phase continues for

several hours, wherein subjective effects decline more slowly than

plasma levels. Most of the pharmacologic effects (i.e., subjective,

cardiovascular, and conjunctival reddening) occur during the initial

20–30 min and last for 4–8 h. Finally, there is a terminal elimination

phase, during which relatively low concentrations of THC and metabolites (primarily THC 11-COOH) leach out from adipose tissues with

a t1/2 ranging from 20–35+ h. Generally, metabolite levels drop below

100 ng/mL within 3–5 days, although considerable variation exists, and

in frequent marijuana users, urinary metabolites can remain detectable

for weeks. High metabolite levels during long leach-out periods in

frequent users typically do not indicate impairment, even when similar

concentrations in occasional users might indicate recent marijuana use

and substantial impairment. This difficulty in correlating THC levels

in biological matrices with behavioral effect has hampered efforts to

regulate marijuana-impaired driving.

PK studies using cannabis edibles have demonstrated only 6–12%

bioavailability. Lipophilic cannabinoids are poorly absorbed in the

water/mucus-rich intestinal environment and are rapidly metabolized

by intestinal and hepatic systems, even before they reach the systemic

circulation. Interestingly, cannabinoids consumed with fatty food

display 200–400% improved bioavailability. Fatty foods stimulate bile

release, which emulsifies fats (and dissolved cannabinoids) to increase

the surface area for absorption. However, fats are not absorbed into

hepatic portal blood but secreted as chylomicrons into lymphatic lacteals, which allows dissolved cannabinoids to bypass hepatic elimination.

Since lymphatic flow is slower than portal blood transport, the higher

cannabinoid bioavailability and slower effect onset in the presence of

fat are overdose risks for the unwary who may consume additional

doses when failing to perceive effects as quickly as expected.

3568 PART 13 Neurologic Disorders

contingency management and cognitive-behavioral and motivational

enhancement therapies for which there is evidence of benefit. Several

studies have found a broad reduction in cannabinoid receptors in the

brain of cannabis users when compared to healthy controls, but receptors recover rapidly, returning to values similar to those of nonusers

after 28 days of abstinence.

Mental Illness An area of major concern is the association between

marijuana use and increased risk for mental illnesses, particularly

psychosis, the risk of which increases with the frequent consumption

of high-THC-content marijuana (>10% content). High-potency marijuana can trigger acute psychotic episodes, which is one of the main

causes for emergency department (ED) visits associated with cannabis

use that can occur even upon first exposure. While most of these

psychotic episodes are transient, with regular marijuana use, they can

become chronic, and in those who are vulnerable, they might trigger

or exacerbate the presentation of schizophrenia. Multiple studies,

although not all, have linked adolescent marijuana use with higher

risk and earlier onset of chronic psychosis, particularly for those using

marijuana at higher frequency or with higher THC content. Furthermore, recent evidence suggests that the difference in the prevalence

of psychosis across different countries may be attributable in part to

the differences in the prevalence of regular use of high-THC-content

marijuana. Concerns have also been raised regarding an association

between marijuana use during adolescence and a higher risk for

depression and suicidality, although these associations have been much

less studied.

Accidents Marijuana use increases the risk of injuries when driving

under its influence. THC impairs judgment, motor coordination, and

reaction time, all of which are necessary for safe driving. Laboratory

studies have found a direct relationship between blood THC levels and

impaired driving ability. Not surprisingly, marijuana use while driving

increases the risk of fatal and nonfatal accidents, and its use while

flying aircraft may have also contributed to increased fatalities among

pilots. However, roadside surveillance of marijuana intoxication has

been difficult to implement because circulating cannabinoid levels do

not correlate with the degree of impairment.

Acute and Chronic Toxicity The increased availability of

high-THC-content products over the past decade has been paralleled

by increased marijuana-related ED visits and hospital admissions.

Such illnesses can be caused by acute toxicity (inappropriate dosing)

and chronic use syndromes. Cannabis edibles represent a significant

portion of acute cannabis toxicity events. Patients include children

accidentally consuming sweet treats and infrequent users such as

“cannabis tourists” with limited experience with consumed products.

As described in the PK section, edibles have a slow onset of effect, and

THC bioavailability can differ greatly when taken on an empty stomach

or with fatty foods. For a variety of reasons, actual dose is also more

difficult to envisage, so naïve or infrequent users are at increased risk

of overdosing. Cannabis toxicity is frequently manifested by severe

anxiety, tachycardia, and even acute psychoses.

Chronic high-dose cannabis use can also induce a cannabis hyperemesis syndrome (CHS), a growing cause for ED and hospital admissions. CHS presents in the ED as severe cycles of nausea, vomiting,

and abdominal pain, but has a prodromal phase of abdominal pain

and nausea that can last several years. CHS does not respond to CB1R

agonist medications such as dronabinol and nabilone that are FDA

approved to treat nausea and vomiting. CHS treatment includes intravenous hydration and proton pump inhibitors for gastritis. Very hot

showers and capsaicin creams are popularly used, but efficacy data are

limited. Droperidol reduces hospital stay times and antiemetic use, but

only cannabis abstinence leads to long-term recovery.

The widespread medicalization of marijuana and its dispensation

outside of the pharmacy system is exposing patients to possible drugdrug interactions (DDIs), potentially without their physician’s or pharmacist’s knowledge. However, the long history of population exposure

has not provided much evidence for cannabis (i.e., THC)–related

DDIs, except for a couple of case studies where THC (metabolized by

■ HARMFUL EFFECTS

The frequency and severity of marijuana’s adverse effects are influenced by the user’s age, dose, frequency of use, route of administration, underlying health status, and genetics. Especially concerning are

the potential negative effects of marijuana on the brain during early

life stages. Perturbation of ECS signaling during early fetal development affects neuronal development, migration, and connectivity. The

relevant studies, which are few and confounded by the frequent use of

other drugs, suggested an association between maternal marijuana use

and fetal growth restriction and preterm delivery but yielded substantial evidence of lower birth weight. As a consequence, the American

College of Obstetricians and Gynecologists recommends discouraging the use of marijuana by women who are pregnant or planning a

pregnancy. Children and adolescents are also more vulnerable to the

harmful effects of marijuana use, which increases markedly during

adolescence and has been associated with lower grades, lower IQ, and

higher risk of dropping out of school, although causality associations

are hindered by poor control of confounding variables. Brain imaging

studies have revealed that use of marijuana at this stage is associated

with structural and functional brain changes often (but findings are

not always replicated) in the form of reduced brain connectivity and

cortical thickness. It is not clear whether these are caused by early

exposure to marijuana, a question that the Adolescent Brain and Child

Development study, a longitudinal neuroimaging, behavioral, and

genetic study of close to 12,000 children in the United States, may be

able to answer. Finally, there is increasing evidence of cardiovascular

adverse effects, including higher risk of myocardial infarction among

cannabis smokers.

Cannabis Use Disorder Repeated marijuana use, especially during adolescence, can result in cannabis use disorder (CUD), which the

fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines as “a problematic pattern of cannabis use leading

to clinically significant impairment or distress.” Use becomes problematic when at least two of the criteria (which include craving, failure to

fulfill role obligations due to recurrent use, tolerance, and withdrawal)

have manifested themselves in a 12-month period. In regular marijuana users, abstinence results in a withdrawal syndrome that manifests within 1–3 days of drug discontinuation as anxiety, restlessness,

insomnia, depression, and reduced appetite. Many of the withdrawal

symptoms resolve within approximately 2 weeks of discontinuation,

but symptoms such as insomnia can persist longer and contribute to

drug taking as a means to combat the symptoms of withdrawal. The

risk of CUD increases with earlier age of initiation, frequency of use,

and exposure to marijuana with high THC content.

PREVENTION Preventing marijuana use during adolescence reduces

the risk for CUD and also the risk for other substance use disorders.

There are several evidence-based prevention strategies focused in

children and adolescents that have shown benefits in decreasing

marijuana use during adolescence or in delaying its age of initiation.

Evidence-based prevention interventions target the individual (e.g.,

Keepin’ It Real, Life Skills, InShape), the family (e.g., Brief Strategic

Family Therapy, Coping Power Program [CPP], Familia Adelante),

and the community (e.g., The Abecedarian Project, Midwestern Prevention Project, Caring School Community). School-based prevention programs are the most widely implemented, and the cumulative

evidence (from randomized controlled trials and prospective cohort

and longitudinal studies) indicates that comprehensive interventions

that include antidrug information with refusal skills, self-management

skills, and social skills training appear to be the most effective

approaches for long-term reduction of marijuana (and alcohol) use in

adolescents.

TREATMENT The treatment of CUD is managed by tapering marijuana use and, in severe cases, by providing support to combat

withdrawal symptoms. The treatment of severe CUD is much more

challenging and requires continuous care. Although there are no U.S.

Food and Drug Administration (FDA)–approved medications for the

treatment of CUD, there are several behavioral interventions, including

3569Opioid-Related Disorders CHAPTER 456

cytochrome P450 [CYP3A, 2C9]) affected a patient’s warfarin levels.

In contrast, the legalization of hemp-derived CBD has made it available at doses never experienced with marijuana. CBD in the Epidiolex

formulation has been FDA approved as a high-dosage (see below)

add-on drug against childhood epilepsies. Recent reports of possible

interactions between CBD and benzodiazepines, methadone, and

the antirejection drug tacrolimus suggest more research is needed to

ensure safety of CBD medications.

■ THERAPEUTIC POTENTIAL

Currently, no FDA-approved medications contain cannabis-derived

THC, although synthetic THC (or dronabinol) is approved for treatment of chemotherapy-induced nausea and appetite stimulation.

Several countries have approved the cannabis-derived THC:CBD

formulation Sativex for treating chronic pain and multiple sclerosis

(MS)–induced spasticity. However, evidence of Sativex efficacy in

MS is largely based on patient reports, with little electromyographic

evidence or physician-scored improvement. Chronic pain is one of

the most frequent indications for which medical marijuana is used,

although the effect is generally modest and possibly related to its

mood-enhancement effects.

High-dose Epidiolex is an FDA-approved oil formulation of CBD

for use as an add-on treatment for Dravet’s and Lennox-Gastaut syndromes and tuberous sclerosis epilepsies. There is clinical evidence for

CBD, at lower doses, as an anxiolytic for the treatment of posttraumatic

stress, anxiety, and relapse of substance use disorders. Animal studies

suggest that this effect of CBD may be mediated by the 5-hydroxytryptamine 1A receptor.

■ FURTHER READING

American College of Obstetricians and Gynecologists

Committee on Obstetric Practice: Committee Opinion No.

637: Marijuana use during pregnancy and lactation. Obstet Gynecol

126:234, 2015.

Hagler DJ Jr et al: Image processing and analysis methods for

the Adolescent Brain Cognitive Development Study. Neuroimage

202:116091, 2019.

Monte AA et al: Acute illness associated with cannabis use, by route

of exposure: An observational study. Ann Intern Med 170:531, 2019.

Patel J, Marwaha R: Cannabis Use Disorder. StatPearls. Treasure

Island, FL, 2020.

Volkow ND et al: Don’t worry, be happy: Endocannabinoids and

cannabis at the intersection of stress and reward. Annu Rev Pharmacol

Toxicol 57:285, 2017.

Opioid analgesics have been used since at least 300 b.c. Nepenthe

(Greek for “free from sorrow”) helped the hero of the Odyssey, but

widespread opium smoking in China and the Near East has caused

harm for centuries. Since the first chemical isolation of opium and

codeine 200 years ago, a wide range of synthetic opioids have been

developed, and opioid receptors were cloned in the 1990s. Two of the

most important adverse effects of all these agents are the development

of opioid use disorder and overdose. Prescription opioids are primarily

used for pain management, but due to ease of availability, individuals

procure and misuse these drugs with dire consequences. In 2015, for

example, 3.8 million individuals in the United States were current

misusers of pain relievers. More concerning, during 2015, >20,000

overdose deaths involved opioids with an additional 12,990 overdose

deaths related to heroin alone. These numbers continue to increase

456 Opioid-Related Disorders

Thomas R. Kosten, Colin N. Haile

TABLE 456-1 Actions of Opioid Receptors

RECEPTOR TYPE ACTIONS

Mu (μ) (e.g., morphine,

buprenorphine)

Analgesia, reinforcement euphoria, cough and

appetite suppression, decreased respirations,

decreased GI motility, sedation, hormone

changes, dopamine and acetylcholine release

Kappa (κ) (e.g., butorphanol) Dysphoria, decreased GI motility, decreased

appetite, decreased respiration, psychotic

symptoms, sedation, diuresis, analgesia

Delta (δ) (e.g., etorphine) Analgesia, euphoria, physical dependence,

hormone changes, appetite suppression,

dopamine release

Nociceptin/orphanin (e.g.,

buprenorphine)

Analgesia, appetite, anxiety, tolerance to

opioids, hypotension, decreased GI motility,

5-HT and NE release

Abbreviations: GI, gastrointestinal; 5-HT, serotonin; NE, norepinephrine.

and have accelerated due to mixing high-potency fentanyl derivatives

with heroin. The accelerating death rates are partially because reversal

of fentanyl overdoses can require severalfold larger doses of naloxone

than the doses in the intranasal devices used for nonmedical street

resuscitations. An additional spike in fentanyl-associated deaths has

also been associated with the COVID-19 pandemic. According to

the most recent World Drug Report, opioid misuse causes the greatest global burden of morbidity and mortality; disease transmission;

increased health care, crime, and law enforcement costs; and less tangible costs of family distress and lost productivity.

The terms dependence and addiction are no longer used to describe

substance use disorders. Opioid-related disorders encompass opioid

use disorder, opioid intoxication, and opioid withdrawal. The diagnosis of opioid use disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), requires the

repeated use of the opiate while producing problems in two or more

areas in a 12-month period. The areas include tolerance, withdrawal,

use of greater amounts of opioids than intended, craving, and use

despite adverse consequences. This new definition of opioid use disorder, reducing the criteria for diagnosis from three problem areas to

two, is not expected to change the rates of these disorders because most

individuals using these substances meet more than three criteria.

A striking recent aspect of illicit opioid use has been its marked

increase as the gateway to illicit drugs in the United States. Since 2007,

prescription opiates have surpassed marijuana as the most common

illicit drug that adolescents initially use, although overall rates of opioid

use are far lower than marijuana. The most commonly used opioids are

diverted prescriptions for oxycodone and hydrocodone, followed by

heroin and morphine, and—among health professionals—meperidine

and fentanyl. Heroin is metabolized into 6-monoacetylmorphine and

morphine thus acting as a prodrug that more readily penetrates the

brain and is converted rapidly to morphine in the body. Two opioid

maintenance treatment agents—methadone and buprenorphine—are

also misused, but at substantially lower rates, and the partial opioid

agonists such as butorphanol, tramadol, and pentazocine are misused

even less frequently. Because the chemistry and general pharmacology

of these agents are covered in major pharmacology texts, this chapter

focuses on the neurobiology and pharmacology relevant to opioid

use disorder and its treatments. Although the neurobiology of misuse

involves all four of the known opioid receptors—mu, kappa, delta, and

nociceptin/orphanin—this discussion focuses on the mu receptor targeted by most of the clinically used opioids.

■ NEUROBIOLOGY

The neurobiology of opioids and their effects not only include opioid

receptors, but also downstream intracellular messenger systems and

ion channels that the receptors regulate. The different functional activities of opioid receptors are summarized in Table 456-1. Abuse liability

of opioids is primarily associated with the mu receptor. All opioid

receptors are G protein–linked and coupled to the cyclic adenosine

monophosphate (cAMP) second messenger system and to G protein–

coupled, inwardly rectifying potassium channels (GIRKs). Opioids

3570 PART 13 Neurologic Disorders

molecular model of NE neuronal activation during withdrawal has had

important treatment implications, such as the use of the α2

-agonist

clonidine to treat opioid withdrawal. Other contributors to withdrawal

include deficits within the dopamine reward system.

■ PHARMACOLOGY

Tolerance and withdrawal commonly occur with chronic daily use,

developing as quickly as 6–8 weeks depending on dose concentration

and dosing frequency. Tolerance appears to be primarily a pharmacodynamic rather than pharmacokinetic effect, with relatively limited

induction of cytochrome P450 or other liver enzymes. The metabolism

of opioids occurs in the liver, primarily through the cytochrome P450

systems of 2D6 and 3A4. They then are conjugated to glucuronic acid

and excreted in small amounts in feces. The plasma half-lives generally

range from 2.5 to 3 h for morphine and >22 h for methadone. The

shortest half-lives of several minutes are for fentanyl-related opioids,

and the longest are for buprenorphine and its active metabolites,

which can block opioid withdrawal for up to 3 days after a single dose.

Tolerance to opioids leads to the need for increasing amounts of drugs

to sustain the desired euphoric effects—as well as to avoid the discomfort of withdrawal. This combination has the expected consequence

of strongly reinforcing misuse once it has started. Methadone taken

chronically at maintenance doses is stored in the liver, which may

reduce the occurrence of withdrawal between daily doses. The role of

endogenous opioid peptides in tolerance and withdrawal is uncertain.

The clinical features of opioid misuse are tied to route of administration and rapidity of the drug reaching the brain. Intravenous and

smoked administration rapidly produces high drug concentrations in

the brain. This produces a “rush,” followed by euphoria, a feeling of

tranquility, and sleepiness (“the nod”). Heroin produces effects that last

3–5 h, and several doses a day are required to forestall manifestations

of withdrawal in chronic users. Symptoms of opioid withdrawal begin

8–10 h after the last dose; lacrimation, rhinorrhea, yawning, and sweating appear first. Restless sleep followed by weakness, chills, gooseflesh

(“cold turkey”), nausea and vomiting, muscle aches, involuntary movements (“kicking the habit”), hyperpnea, hyperthermia, and hypertension occur in later stages of the withdrawal syndrome. The acute course

of withdrawal may last 7–10 days. A secondary phase of protracted

abstinence lasts for 26–30 weeks and is characterized by hypotension,

bradycardia, hypothermia, mydriasis, and decreased responsiveness of

the respiratory center to carbon dioxide.

Besides the brain effects of opioids on sedation and euphoria and

the combined brain and peripheral nervous system effects on analgesia, a wide range of other organs can be affected. The release of several

activate GIRKs, increasing permeability to potassium ions to cause

hyperpolarization, which inhibits the production of action potentials.

Thus, opioids inhibit the activity of diverse and widely distributed

neuronal types. The major effects of opioids, such as analgesia, sedation, and drug reinforcement, are produced through this inhibition of

neurons that belong to specific brain pathways.

Many opioid actions are related to the specific neuroanatomic locations of mu receptors. Reinforcing and euphoric effects of opioids relate

primarily to activation of the mesolimbic dopaminergic pathway from

the ventral tegmental area (VTA) to the nucleus accumbens (NAc),

where opioids increase synaptic levels of dopamine. This increase is

due to inhibition of GABAergic neurons that inhibit the activity of

neurons within both the VTA and the NAc. The positive subjective

effects of opioid drugs also include mu receptor desensitization and

internalization, potentially related to stimulation of β-arrestin signaling pathways. However, the “high” only occurs when the rate of change

in dopamine is fast. Large, rapidly administered doses of opioids block

γ-aminobutyric acid (GABA) inhibition and produce a burst of VTA

dopamine neuron activity that is associated with a “high” in commonly

misused substances. Therefore, routes of administration that slowly

increase opioid blood and brain levels, such as oral and transdermal

routes, are effective for analgesia and sedation but do not produce an

opioid “high” that follows smoking and intravenous routes. Other acute

effects such as analgesia and respiratory depression involve opioid

receptors located in other brain areas such as the locus coeruleus (LC).

Opioid tolerance and withdrawal are chronic effects related to the

cAMP-protein kinase A (PKA)-cAMP response-element binding protein (CREB) intracellular cascade (Fig. 456-1). These effects are also

reflective of genetic risk factors for developing opioid use disorder,

with estimates of up to 50% of the risk due to polygenic inheritance.

Specific functional polymorphisms in the mu opiate receptor gene

appear to be associated with this risk for opioid misuse, including one

producing a threefold increase in this receptor’s affinity for opiates and

the endogenous ligand β-endorphin. Epigenetic methylation changes

also occur on DNA in the region of the mu receptor gene in individuals

with opioid use disorder, inhibiting gene transcription. This molecular

cascade links acute intoxication and sedation to opioid tolerance and

withdrawal mediated by the LC. Noradrenergic (NE) neurons in the

LC mediate activation of the cortical hemispheres. When large opioid

doses saturate and activate all of its mu receptors, action potentials

cease. When this direct inhibitory effect is sustained over weeks and

months of opioid use, a secondary set of adaptive changes occur that

lead to tolerance and withdrawal symptoms (Fig. 456-1). Withdrawal

symptoms reflect, in part, overactivity of NE neurons in the LC. This

β-endorphin

enkephalins

K+

Na+ Na+

K+

µ µ

Gi/o Gi/o

AC

cAMP cAMP

Nucleus Nucleus PKA PKA

BDNF BDNF TH TH

CREB CREB

N CH3

H

H

HO

O

HO

Morphine

A B

AC

Modified gene

expression,

neuroplasticity,

genetic effects

FIGURE 456-1 Normal mu-receptor activation by endogenous opioids inhibits the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP responseelement binding protein (CREB) cascade in noradrenergic neurons within the locus coeruleus (A) through inhibitory Gi/o protein influence on adenylyl cyclase (AC).

Similarly, acute exposure to opioids (e.g., morphine) inhibits this system, whereas chronic exposure to opiates (B) leads to upregulation of the cAMP pathway in an attempt

to oppose opioid-induced inhibitory influence. Upregulation of this system is involved in opioid tolerance, and when the opioid is removed, unopposed noradrenergic

neurotransmission is involved in opioid withdrawal. Upregulated PKA phosphorylates CREB, initiating the expression of various genes such as tyrosine hydroxylase (TH)

and brain-derived neurotrophic factor (BDNF). BDNF is implicated in long-term neuroplastic changes in response to chronic opioids.

3571Opioid-Related Disorders CHAPTER 456

pituitary hormones is inhibited, including corticotropin-releasing

factor (CRF) and luteinizing hormone, which reduces levels of cortisol and sex hormones and can lead to impaired stress responses and

reduced libido. An increase in prolactin also contributes to the reduced

sex drive in males. Two other hormones affected are thyrotropin,

which is reduced, and growth hormone, which is increased. Respiratory depression results from opioid-induced insensitivity of brainstem

neurons to increases in carbon dioxide, and in patients with pulmonary

disease, this can result in clinically significant complications. In overdoses, aspiration pneumonia is common due to loss of the gag reflex.

Opioids reduce gut motility, which is helpful for treating diarrhea,

but can lead to nausea, constipation, and anorexia with weight loss.

Deaths occurred in early methadone maintenance programs due to

severe constipation and toxic megacolon. Opioids such as methadone

may prolong QT intervals and lead to sudden death in some patients.

Orthostatic hypotension may occur due to histamine release and

peripheral blood vessel dilation, which is an opioid effect usefully

applied to managing acute myocardial infarction. During opioid

maintenance, interactions with other medications are of concern; these

include inducers of the cytochrome P450 system (usually CYP3A4)

such as rifampin and carbamazepine.

Heroin users in particular tend to use opioids intravenously and are

likely to be polydrug users, also using alcohol, sedatives, cannabinoids,

and stimulants. None of these other drugs are substitutes for opioids,

but they have desired additive effects. Therefore, one needs to be sure

that the person undergoing a withdrawal reaction is not also withdrawing from alcohol or sedatives, which might be more dangerous and

more difficult to manage.

Intravenous opioid use carries with it the risk of serious complications. The common sharing of hypodermic syringes can lead to

infections with hepatitis B and HIV/AIDS, among others. Bacterial

infections can lead to septic complications such as meningitis, osteomyelitis, and abscesses in various organs. Off-target effects of opioids

synthesized in illicit drug labs can lead to serious toxicity. For example,

attempts to illicitly manufacture meperidine in the 1980s resulted in

the production of a highly specific neurotoxin, MPTP, which produced

parkinsonism in users (Chap. 435).

Lethal overdose is a relatively common complication of opioid

use disorder. Rapid recognition and treatment with naloxone, a

highly specific reversal agent that is relatively free of complications,

are essential. The diagnosis is based on recognition of characteristic

signs and symptoms, including shallow and slow respirations, pupillary miosis (mydriasis does not occur until significant brain anoxia

supervenes), bradycardia, hypothermia, and stupor or coma. Blood

or urine toxicology studies can confirm a suspected diagnosis, but

immediate management must be based on clinical criteria. If naloxone is not administered, progression to respiratory and cardiovascular collapse leading to death occurs. At autopsy, cerebral edema and

sometimes frothy pulmonary edema are generally found. Opioids

generally do not produce seizures except for unusual cases of polydrug use with the opioid meperidine, with high doses of tramadol, or

in the newborn.

TREATMENT

Opioid Overdose

Beyond the acute treatment of opioid overdose with naloxone,

clinicians have two general treatment options: opioid maintenance

or detoxification. Opioid agonist and partial agonist medications

are commonly used for both maintenance and detoxification

purposes. α2

-Adrenergic agonists are primarily used for detoxification. Antagonists are used to accelerate detoxification and

then continued after detoxification to prevent relapse. Only the

residential medication-free programs have had success that comes

close to matching that of the medication-based programs. Success

of the various treatment approaches is assessed as retention in

treatment and reduced opioid and other drug use; secondary

outcomes, such as reduced HIV risk behaviors, crime, psychiatric symptoms, and medical comorbidity, also indicate successful

treatment.

Stopping opioid use is much easier than preventing relapse.

Long-term relapse prevention for individuals with opioid use disorder requires combined pharmacologic and psychosocial approaches.

Chronic users tend to prefer pharmacologic approaches; those with

shorter histories of drug use are more amenable to detoxification

and psychosocial interventions.

OPIOID OVERDOSE

Managing overdose requires naloxone and support of vital functions, including intubation if needed (Table 456-2). If the overdose

is due to buprenorphine, then naloxone might be required at total

doses of 10 mg or greater, but primary buprenorphine overdose

is nearly impossible because this agent is a partial opioid agonist,

meaning that as the dose of buprenorphine is increased it has greater

opioid antagonist than agonist activity. Thus, a 0.2-mg buprenorphine

dose leads to analgesia and sedation, while a hundred times greater

20-mg dose produces profound opioid antagonism, precipitating

opioid withdrawal in a person who had opioid use disorder on

morphine or methadone. It is important to recognize that the goal is

to reverse the respiratory depression and not to administer so much

naloxone that it precipitates opiate withdrawal. Because naloxone

only lasts a few hours and most opioids last considerably longer, an

IV naloxone drip with close monitoring is frequently employed to

provide a continuous level of antagonism for 24–72 h depending

on the opioid used in the overdose (e.g., morphine vs methadone).

Whenever naloxone has only a limited effect, other sedative drugs

that produce significant overdoses must be considered. The most

common are benzodiazepines, which have produced overdoses and

deaths in combination with buprenorphine. A specific antagonist

for benzodiazepines—flumazenil at 0.2 mg/min—can be given to

a maximum of 3 g/h, but it may precipitate seizures and increase

intracranial pressure. Like naloxone, administration for a prolonged period is usually required because most benzodiazepines

remain active for considerably longer than flumazenil. Support of

vital functions may include oxygen and positive-pressure breathing, IV fluids, pressor agents for hypotension, and cardiac monitoring to detect QT prolongation, which might require specific

treatment. Activated charcoal and gastric lavage may be helpful

for oral ingestions, but intubation will be needed if the patient is

stuporous.

OPIOID WITHDRAWAL

The principles of detoxification are the same for all drugs: to substitute a longer-acting, orally active, pharmacologically equivalent

medication for the substance being used, stabilize the patient on

that medication, and then gradually withdraw the substituted medication. Methadone and buprenorphine are the two medications

used to treat opioid use disorder. Clonidine, a centrally acting

sympatholytic agent, has also been used for detoxification in the

United States. By reducing central sympathetic outflow, clonidine

mitigates many of the signs of sympathetic overactivity but typically

requires augmentation with other agents. Clonidine has no narcotic

action and is not addictive. Lofexidine, a clonidine analogue with

less hypotensive effect, is not yet approved in the United States.

TABLE 456-2 Management of Opioid Overdose

Establish airway. Intubation and mechanical ventilation may be necessary.

Naloxone 0.4–2.0 mg (IV, IM, or endotracheal tube). Onset of action with IV is

~1–2 min.

Repeat doses of naloxone if needed to restore adequate respiration or a

continuous infusion of naloxone can be used.

One-half to two-thirds of the initial naloxone dose that reversed the respiratory

depression is administered on an hourly basis (note: naloxone dosing is not

necessary if the patient has been intubated).

3572 PART 13 Neurologic Disorders

Methadone for Detoxification Dose-tapering regimens for detoxification using methadone range from 2–3 weeks to as long as

180 days, but this approach is controversial given the relative effectiveness of methadone maintenance and the low success rates of

detoxification. Unfortunately, the vast majority of patients tend to

relapse to heroin or other opioids during or after the detoxification

period, indicative of the chronic and relapsing nature of opioid use

disorder.

Buprenorphine for Detoxification Buprenorphine does not appear

to lead to better outcomes than methadone but is superior to clonidine in reducing symptoms of withdrawal, in retaining patients in a

withdrawal protocol, and in completing treatment.

`2

-Adrenergic Agonists for Detoxification Several α2

-adrenergic

agonists have relieved opioid withdrawal by suppressing brain NE

hyperactivity. Clonidine relieves some signs and symptoms of opioid withdrawal such as lacrimation, rhinorrhea, muscle pain, joint

pain, restlessness, and gastrointestinal symptoms. Related agents are

lofexidine, guanfacine, and guanabenz acetate. Lofexidine can be

dosed up to ~2 mg/d and appears to be associated with fewer adverse

effects. Clonidine or lofexidine is typically administered orally, in

three or four doses per day, with dizziness, sedation, lethargy, and

dry mouth as the primary adverse side effects. Outpatient-managed

withdrawal will require close follow-up, often with naltrexone

maintenance to prevent relapse.

Rapid and Ultrarapid Opioid Detoxification The opioid antagonist naltrexone typically combined with an α2

-adrenergic agonist

has been purported to shorten the duration of withdrawal without significantly increasing patient discomfort. Completion rates

using naltrexone and clonidine range from 75 to 81% compared

to 40 to 65% for methadone or clonidine alone. Ultrarapid opioid

detoxification is an extension of this approach using anesthetics

but is highly controversial due to the medical risks and mortality

associated with it.

Opioid 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.