PHARMACOKINETICS/DYNAMICS, NEUROBIOLOGY, AND EPIDEMIOLOGY
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 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 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.
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.
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).
TABLE 447-1Complications of Cocaine Use ||Download (.pdf) TABLE 447-1 Complications of Cocaine Use
|Cardiovascular || |
Increased myocardial oxygen demand
Increased vascular shearing forces
Left ventricular dysfunction/heart failure (high blood concentrations)
Supraventricular and ventricular dysrhythmias
|Central and Peripheral Nervous || |
|Pulmonary || |
Pharyngeal burns (inhaled)
Reversible airway disease exacerbations
Shortness of breath (“crack lung”)
|Gastrointestinal || |
Impaction (body packing)
Hepatic enzyme elevation
|Renal || |
|Endocrine || |
|Other || |
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.
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 Psychostimulants COCAINE ACUTE INTOXICATION
As with all emergency situations the first task is to ensure a patent 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 noncocaine-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 also 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 cocaine-related mortality have been associated with concurrent use of other illicit drugs (particularly heroin), the physician must be prepared to institute effective emergency treatment for multiple drug toxicities. COCAINE USE DISORDERS
Treatment of cocaine use disorders requires the combined efforts of primary care physicians, psychiatrists, and psychosocial care providers. Early abstinence from cocaine 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.
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. 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). Vaccines for cocaine and methamphetamine use disorders are also being developed. Finally, recent preliminary studies have brought attention to the 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 are warranted.