Chapter 447: Cocaine and Other Commonly Used Drugs

The use of cocaine and other psychostimulants 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. Polydrug use involving the concurrent use of several drugs with different pharmacologic effects is increasingly 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-maintained patients. Some forms of polydrug use, such as the combined use of IV heroin and cocaine, are especially dangerous and account for many hospital emergency room visits. Chronic cocaine and psychostimulant use may cause a number of adverse health consequences and may 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 drug 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.

Stimulants and hallucinogens have been used to induce euphoria and alter consciousness for centuries. Cocaine and marijuana are two of the most commonly used drugs today. Synthetic variations of marijuana and a variety of 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; as well as hallucinogens such as phencyclidine (PCP), D-lysergic acid diethylamide (LSD), salvia divinorum; and marijuana and the synthetic cannabinoids. Some options for medical management of severe adverse effects are also described.

PHARMACOKINETICS/DYNAMICS, NEUROBIOLOGY, AND EPIDEMIOLOGY

Cocaine

Cocaine is a powerful stimulant 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.

Cocaine comes in a variety of forms, the most commonly 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 intravenously. When used intranasally the bioavailability of cocaine is about 60 per percent. 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 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.

Given the extensive pulmonary vasculature, smoked or inhaled cocaine reaches the brain very quickly and produces a rapid and intense (yet 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, 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.

According to the National Survey on Drug Use and Health (NSDUH), in 2015 about 1.9 million people (~0.7% of the population) were current users of cocaine, including about 394,000 current users of crack (0.1% of the population in the United States). There were 53,000 adolescents aged 12–17 (0.2% of adolescents) who were current users of cocaine in 2015. About 896,000 people aged ≥12 (0.3% of the population) in 2015 had a cocaine use disorder in the past year. The Drug Abuse Warning Network (DAWN) reported that in 2011 there were 505,224 cocaine-related emergency department (ED) visits, or about 162 ED visits per 100,000 of the U.S. population.

Methamphetamine

Methamphetamine is a stimulant 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. 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 to 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, serotonin, 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 and more efficacious 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.

According to the NSDUH, ~897,000 people (0.3% of the population) aged ≥12 were current users of methamphetamine in 2015. Meanwhile, about 13,000 adolescents (0.1%) aged 12–17 were current methamphetamine users in 2015. There were also 51.3 ED visits, per 100,000 of the population, related to illicit stimulants (predominately amphetamines and methamphetamine) in 2011.

MDMA and Cathinones

MDMA is an illegal drug that has stimulant and psychedelic effects. 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 experience. MDMA is usually taken orally in a tablet, capsule, or liquid form, and its effects last ~3–6 h. MDMA alters brain chemistry by binding to serotonin transporters and increasing 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 in terminally ill patients, and for social anxiety in autistic adults.

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. The Monitoring the Future study estimated that, in 2016, the lifetime prevalence of MDMA use among eighth graders was 1.7%, tenth graders was 2.8%, and twelfth graders was 4.9%, with the most use among 18–25 year olds.

Cathinone is an alkaloid psychostimulant found in the khât (Catha edulis) plant, which grows at high altitudes in East Africa and the Middle East. The actions and effects of khât are like those of the amphetamines, and misusers are at 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.

Prescribed Psychostimulants

Methylphenidate, amphetamine, and methamphetamine are psychostimulants approved in the United States for treatment of attention-deficit hyperactivity disorder (ADHD), weight control, and narcolepsy. 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. These drugs deserve mention here, as there has been increased use of nonprescribed amphetamines or methylphenidate as a study aid among college students, and an energy and productivity booster for so-called “supermoms.” According to the NSDUH, of the 7.7 million people, aged ≥12, who had a past year stimulant use disorder (SUD) related to their use of illicit drugs, 0.4 million misused prescription stimulants.

CLINICAL MANIFESTATIONS

Psychostimulants produce the same acute CNS effects: euphoria, increased energy/decreased fatigue, reduced need for sleep, decreased appetite, decreased distractibility, increased self-confidence and alertness, 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 may include impotence, gynecomastia, menstrual function disruptions, and persistent hyperprolactinemia (Table 447-1).

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. 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. Psychostimulant withdrawal is not thought to be a driver of ongoing use. Debate remains as to whether, in psychostimulant withdrawal, symptoms decline monotonically or occur in discrete phases, getting worse before they get better. Most current theories of psychostimulant addiction emphasize the primary role of conditioned craving, which can persist long after physiological withdrawal has abated.

Injection of psychostimulants places people at increased risk of contracting infectious diseases from exposure to blood or other bodily fluids, such as HIV and hepatitis B and C. 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.

SCREENING AND DIAGNOSIS

The Diagnostic and Statistical Manual of Psychiatric Disorders, 5th edition (DSM-5) defines a 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 two 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 cut down or control; 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.

TREATMENT

Hallucinogens are a diverse group of drugs causing alteration of thoughts, feelings, sensations, and perceptions. Their use in religious and spiritual rituals goes back centuries. Hallucinogens can be found naturally in plants and mushrooms, or can be human-made. 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-phosphoryloxy-N,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 include: DXM (an over-the-counter cough suppressant, when used in high doses); ketamine (a human and veterinary anesthetic); PCP (cyclohexylamine derivative and dissociative anesthetic); and Salvia divinorum (salvia, a Mexican, Central, and South American plant).

Hallucinogens are used in a wide variety of ways, including smoking, snorting, and transmucosally. Except for salvia, whose effects last 30 min, the onset of action of hallucinogens is within 20–90 min and the duration of action can be as long as 6–12 h. Hallucinogens disrupt brain chemistry, specifically 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 2015, an estimated 1.2 million (0.5%) of people aged ≥12 reported current hallucinogen use. The highest rates were among young adults aged 18–25, with 1.8% (636,000) young adults reporting current hallucinogen use.

Clinical manifestations of hallucinogen use include: 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. “Bad trips” (negative experiences with hallucinogen use) can include panic, paranoia, and psychosis, and may persist for up to 24 h. Such experiences are best treated with supportive reassurance. There is some evidence that chronic effects of hallucinogen use can occur, including persistent psychosis, memory loss, anxiety, depression, and flashbacks.

There are currently no FDA-approved medications for the treatment of hallucinogen addiction. Research on behavioral treatments for hallucinogen addiction is underway.

Marijuana policies in several states in the United States have legalized marijuana for medical and/or recreational use. Marijuana refers to the dried leaves, flowers, stems, and seeds from the hemp plant, Cannabis sativa. There are >480 natural components found within the Cannabis sativa plant, of which 66 have been classified as “cannabinoids”; chemicals unique to the plant. The degree of psychological activity allows for the differentiation of the cannabinoids. Three classes of cannabinoids, the cannabigerols (CBGs), cannabichromenes (CBCs), and cannabidiols (CBDs) are not known to have psychological effects. The psychologically active cannabinoids include: tetrahydrocannabinols (THC), cannabinol (CBN), and cannabinodiol (CBDL), among other cannabinoids. Delta-9-tetrahydrocannabinol (THC) is the main psychoactive chemical, responsible for most of the intoxicating effects. Stronger forms of marijuana include sinsemilla (from specially tended female plants) and concentrated resins, including honey-like hash oil, waxy budder, and hard amber-like shatter.

When smoked, marijuana is quickly absorbed from the lungs into the blood and then sequestered in tissues and metabolized by the liver. Marijuana can also be baked into foods (edibles) and eaten with a resulting slower onset of action of 30–60 min. Cannabinoid receptors (CB₁ and CB₂) have been identified in the CNS (cerebral cortex, basal ganglia, and hippocampus) and PNS, as well as on T and B lymphocytes. Endogenous cannabinoids (such as anandamide) as well as exogenous cannabinoids (THC) bind to the CB₁ receptors. Cannabinoid effects occur in the limbic system, affecting memory, cognition and psychomotor performance, and the mesolimbic pathway, impacting the reward pathway and areas of pain perception. Effects include: altered senses, altered sense of time, laughter, changes in mood, psychomotor retardation, difficulty with thinking and problem-solving, and impaired memory.

Marijuana is the most commonly used illicit drug in the United States, with 22.2 million (8.3%) current marijuana users aged ≥12 (i.e., users in the past 30 days). In 2015, >11 million young adults, ages 18–25, used marijuana in the past year, and 19.8% used in the past month. Of the 7.7 million people aged ≥12 who had a past year SUD related to their use of illicit drugs, 4.0 million had a past year disorder related to their use of marijuana. In 2015, 2.6% of adolescents aged 12–17, 5.1% of young adults aged 18–25, and 0.8% of adults aged ≥26 had a marijuana use disorder in the past year. Emergency room visits involving marijuana have increased, which may be due to increased THC levels in marijuana over the past few decades resulting in a greater chance of a harmful reaction.

Acute intoxication brings with it a perceived sense of relaxation and mild euphoria, accompanied by some degree of impairment in memory, concentration, judgment, and perceptual and psychomotor function, as well as anxiety, paranoia, and rarely, psychosis. As with all psychoactive compounds, the experience changes depending on the individual’s environment and state of mind at the time of use. Physical signs of marijuana use include conjunctival injection and tachycardia. Adverse physical effects of marijuana include: respiratory problems due to inhaled pulmonary irritants and lower birth weights in pregnancy.

Chronic marijuana use may also have adverse psychological effects, which may not be permanent, such as impaired concentration and learning, insomnia, and worsening symptoms in schizophrenia. Upon cessation, or cutting back, there is evidence of a withdrawal syndrome consisting of irritability, insomnia, anorexia, anxiety, and craving. Individuals who begin marijuana use before age 17, while the brain is still developing, may be more prone to cognitive deficits, and may be at higher risk for polydrug addiction in the future.

There are no current medications to treat marijuana use disorder. Behavioral therapies (CBT, CM, MET) and symptomatic treatment of withdrawal, for example selective serotonin reuptake inhibitors (SSRIs) to treat related anxiety, may be effective. Preliminary studies and small clinical trials with zolpidem (sleep aid), buspirone (antianxiety/antistress medication), and gabapentin (antiepileptic) have been promising. Other agents being studied include N-acetylcysteine; fatty acid amid hydrolase (FAAH) inhibitors, which may reduce withdrawal by inhibiting the breakdown of endocannabinoids; and allosteric modulators that interact with cannabinoid receptors to inhibit THC’s rewarding effects.

Therapeutic use of marijuana includes as an antiemetic in chemotherapy, appetite promoter in AIDS, intraocular pressure reducer in glaucoma, and spasticity reducer in multiple sclerosis and other neurologic disorders.

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 that are chemically like 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 get other drugs, such as synthetic cathinones. The uncertainty of what is actual 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 they 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 to 45 min, and a duration of action that varies from 2 to 7 h. A recent study found that MDPV affects the brain in a manner similar to cocaine, but is at least 10 times more powerful. 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.

Synthetic cannabinoids refer to a growing number of human-made psychoactive chemicals that are either sprayed on dried, shredded plant material so they can be smoked (herbal incense), or sold as liquids to be vaporized and inhaled in e-cigarettes and other devices (liquid incense). Synthetic cannabinoids act on the same brain cell receptors as THC, the psychoactive ingredient in marijuana, and with use people report elevated mood, relaxation, altered perception, and symptoms of psychosis, including extreme anxiety, confusion, paranoia, and hallucinations.

Overdose with synthetic cannabinoids can result in tachycardia, vomiting, violent behavior, and suicidal thoughts. Elevations in blood pressure due to vasoconstriction can impair blood flow to the heart, brain, kidney, liver, and other vital organs. Withdrawal symptoms include: headaches, anxiety, depression, and irritability. Behavioral and pharmacologic therapies for treatment of synthetic cannabinoid addiction have not yet been tested.

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

Cannabis remains the most commonly used drug globally, with an estimated 183 million people having used the drug in 2014, while amphetamines are the second most commonly used drug. Overall global trends show the use of cannabis has remained stable over the past 3 years; however, in subregions of North America and Western and Central Europe, cannabis use has increased. Cocaine use had remained stable until 2010 when it also began to rise, driven by an increase in cocaine use in South America. The use of amphetamines appears to be stable; however, drug use data may be an underestimate particularly in subregions in East and South-East Asia, where information is sparse. Globally, men are three times more likely than women to use cannabis, cocaine, or amphetamines, whereas women are more likely than men to participate in the nonmedical use of opioids and tranquilizers. Opioids, cocaine, amphetamines, and cannabis together accounted for almost 12 million life years lost due to premature death or disability in 2013 according to the United Nation’s World Drug Report 2016. Stigma and marginalization makes treatment of drug use disorders difficult and hinders sustainable development incorporating gender equality and the empowerment of women and girls. Drug use further corrodes environmental and economic well-being as well as the ability to develop and sustain safe communities.

Despite their prevalence and public health impact, psychostimulant, hallucinogen, and marijuana use disorders have no FDA-approved treatment medications. While behavioral therapies such as CBT, CM, and MET have been shown effective in psychostimulant use disorders, further research needs to be done regarding their utility for hallucinogen and marijuana 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 pharmacological 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), optogenetic techniques (use of light to control neurons that have been genetically modified to express light-sensitive ion channels), wearable biosensors, and mobile technology, including ecological and geographical momentary assessment (EMA/GMA) as well as real-time interventions delivered via smartphone or other mobile devices.