Effects of Drug Abuse on the Nervous System

Opioids

Opioids include agonists, antagonists, and mixed agonist–antagonists ( Box 87.1 ). In the past, the opioid most often used recreationally was heroin (diacetylmorphine), which is classified by the US Drug Enforcement Agency (DEA) as Schedule I (high potential for abuse, no accepted medical use).

Beginning in the 1990s, the United States and other countries experienced a steady rise in the use of prescription opioids to treat chronic noncancer pain ( ). There soon emerged an epidemic of recreational use of these products ( ; ), which in turn was followed by an epidemic of illicit opioid use, including heroin, fentanyl, and “designer opioids” (principally fentanyl analogs and novel synthetic opioids) ( ). These agents are often taken with other drugs, including cocaine, benzodiazepines, and ethanol. Of 72,306 drug overdose deaths in the United States during 2017, 84% were opioid-related ( ).

Desomorphine, a designer opioid, has become increasingly popular in Eastern Europe. Termed “crocodile” for the green-black skin lesions found on parenteral users, the drug is made by cooking crushed codeine pills with household hydrocarbons such as gasoline or paint thinner. Vascular damage causes gangrene and multiorgan failure, and average life expectancy in users is estimated at 2 years ( ). Since 2013, undocumented reports of crocodile use in North America have appeared ( ).

Kratom, obtained from a Southeast Asian tree, contains mitragynine, which has opioid-like as well as serotonergic and noradrenergic effects. Usually smoked, Kratom produces stimulatory effects at low doses and opioid effects at higher doses ( ). Fatal overdose has been reported ( ).

At desired levels of intoxication, opioid agonists produce drowsy euphoria, analgesia, cough suppression, miosis, and often a variety of other symptoms and signs ( Box 87.2 ). Taken parenterally or smoked, heroin produces a “rush,” a brief ecstatic feeling followed by euphoria and either “nodding” or garrulous hyperactivity.

Heroin overdose causes coma, respiratory depression, and pinpoint but reactive pupils; hypotension, if present, is usually secondary to hypoventilation. Treatment of overdose, including naloxone and ventilator support, depends on the degree of respiratory depression ( Box 87.3 ). Fentanyl, fentanyl analogs, and novel synthetic opioids, some of which are thousands of times more potent than morphine, require larger and often repeated doses of naloxone to reverse respiratory depression. In response to the opioid epidemic, naloxone is now available over the counter as a nasal spray or an auto-injector.

Opioid agonist withdrawal produces a characteristic syndrome ( Box 87.4 ). Seizures and delirium are not features, and their presence mandates identification of another cause (e.g., cocaine overdose or ethanol withdrawal). Craving is intense and is not explained by the unpleasantness of the somatic symptoms. Opioid withdrawal in adults is seldom life-threatening and can usually be prevented or treated with methadone 20 mg taken once or twice daily. With morphine or heroin, withdrawal symptoms usually appear several hours after the last dose, peak at 24–72 hours, and last a week or two. With methadone, symptoms appear at 12–24 hours and can last several weeks.

In newborns, untreated opioid withdrawal is severe, protracted, and often fatal. Seizures and myoclonus are described but can be difficult to tell from jitteriness. Treatment is with titrated doses of methadone or paregoric. Phenobarbital can be added for intractable seizures or if additional drug withdrawal is suspected.

Opioid dependence is treated pharmacologically with maintenance doses of methadone or buprenorphine ( ; ). Treatment failure is most often attributable to inadequate dosage. Despite US Food and Drug Administration (FDA) approval, oral treatment with the opioid antagonist naltrexone has limited usefulness in treating opioid dependence ( ; ). Proposed alternative therapies include injectable extended-release naltrexone ( ), slow-release oral morphine ( ), injectable heroin ( ), acupuncture ( ), and deep brain stimulation ( ). Treatment with the West African hallucinogenic alkaloid ibogaine has been associated with sudden cardiac death ( ).

Psychostimulants

Psychostimulants comprise a large number of licit and illicit drugs that include cocaine and amphetamine-like agents ( Box 87.5 ) .

Cocaine is an alkaloid present in the South American plant Erythroxylon coca . Unlike other psychostimulants, cocaine is also a local anesthetic. As a street drug, cocaine hydrochloride is sniffed or injected. An alkaloidal preparation (“crack”) is smoked, thereby avoiding complications of parenteral use and allowing sustained administration of very large doses. Methamphetamine (“speed,” “crystal meth”) is easily manufactured from commercially available pseudoephedrine. In the United States it is especially popular in midwestern and rural areas. Methamphetamine can be taken orally, sniffed, injected, or, as “ice,” smoked. During 2010 it was estimated that worldwide 17.9 million people were dependent on amphetamine-like psychostimulants and 6.7 million on cocaine ( ).

Intended effects of cocaine and methamphetamine include alert euphoria with increased motor activity and endurance. Taken parenterally or smoked, they produce a rush distinguishable from that of opioids. With repeated use there is stereotypic activity progressing to bruxism and dyskinesias and paranoia progressing to frank hallucinatory psychosis.

Cocaine or methamphetamine overdose causes psychiatric, cardiopulmonary, and neurological symptoms, which can progress to shock, coma, and death ( Box 87.6 ). Malignant hyperthermia and disseminated intravascular coagulation occur. Treatment includes sedation, cooling, anticonvulsants, antihypertensives, and cardiac monitoring ( Box 87.7 ) .

Withdrawal from these agents produces fatigue, hunger, craving, and depression. Objective signs are few, but depression can be suicidal.

The phenylalkylamine 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”), popular on college campuses, appears to combine the psychostimulant properties of amphetamine-related agents and the hallucinogenic properties of drugs such as d -lysergic acid diethylamide (LSD). Many analogs of MDMA are marketed for oral use. At low doses, MDMA reportedly facilitates communication and empathy. Undesired effects include anxiety, tremor, muscle tightness, sweating, profuse salivation, blurred vision, and ataxia. As with methamphetamine, overdose causes hypertensive crisis, hyperthermia, tachyarrhythmia, psychosis, delirium, seizures, and rhabdomyolysis. Treatment is similar to that for psychostimulant toxicity.

Khat, a shrub indigenous to East Africa and the Arabian Peninsula, contains an amphetamine-like compound, cathinone, and the plant’s leaves are chewed for their stimulant effects. During the past decade “designer” analogs of cathinone have become popular recreational drugs in Europe and North America. Purchased through the Internet as “legal highs” and collectively marketed as “bath salts,” dozens of compounds are available, including methcathinone (ephedrone), mephedrone, methylone, and methylenedioxypyrovalerone (MDPV) ( ; ; ; ; ; ; ). Overdose is similar to what is encountered with methamphetamine. Numerous fatalities have been reported ( ).

In addition to cathinone derivative, a wide array of novel designer psychostimulants have appeared on European and North American markets. Chemically characterized as aminoindanes, piperazines, and pipradrol, these agents have varying degrees of noradrenergic, dopaminergic, and serotonergic activity, and some are used as MDMA substitutes in products sold as Ecstasy ( ; ; ).

Phenylpropanolamine, an amphetamine-like compound, was present in decongestants and diet pills and also available on the Internet as a “legal high” until a case-control study demonstrated it carried a risk for stroke. It was withdrawn from the US market in 2000 ( ).

Dietary supplements containing ephedra alkaloids (“ma huang”) were available in “health food” stores until stroke and seizure risk led to their withdrawal in 2003 ( ).

Despite clinical trials involving dozens of agents, an effective pharmacotherapy for psychostimulant dependence does not exist. Studies have involved dopamine, serotonin, opioid agonists and antagonists ( ), GABAergic agents (modify effects of γ-aminobutyric acid [GABA]), glutamate inhibitors ( ), sigma receptor ligands ( ), calcium channel blockers, ketamine ( ), glial modulators ( ), bupropion ( ), guanfacine ( ), metyrapone ( ), salvinorin A analogs ( ), N -acetylcysteine ( ; ), orexin antagonists ( ), and deep brain stimulation ( ).