Designer drugs in children and adolescents

Cynthia C Hoecker, MD

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INTRODUCTION — "Designer drugs" are synthetic derivatives of federally controlled substances, created by slightly altering the molecular structure of existing drugs, and are produced illegally in clandestine laboratories for illicit use [1]. Many of the most popular designer drugs on the street today are amphetamine analogs. Most of these drugs have some psychoactive properties and cause visual disturbances, but they are not true hallucinogens like lysergic acid diethylamide (LSD) [2].

Legislation was passed in the mid-1980s that made it illegal to manufacture, sell, or possess designer drugs in the United States. Despite this legislation, the synthesis, sale, and use of designer drugs have increased among teenagers and young adults, creating a considerable public health and law enforcement problem.

The street names, clinical effects, and management of intoxication of the most commonly used designer drugs are reviewed here. The use and treatment of other illicit substances are discussed separately. (See "Cocaine: acute intoxication").

AMPHETAMINE ANALOGS — Amphetamine analogs are the most popular designer drugs. They are synthesized by attaching various substituents (including methoxy, methyl, halogen, or sulfur) to different positions of the phenyl ring of amphetamine or methamphetamine (show figure 1) [1].

Designer amphetamines — The most widely used amphetamine analogs include methylenedioxymethamphetamine (MDMA, ecstasy), methamphetamine (ice, crystal), methylenedioxyamphetamine (MDA, the love pill), and methylenedioxyethamphetamine (MDEA, Eve).

MDMA — MDMA (methylenedioxymethamphetamine) is one of the most commonly used designer drugs today. Additional street names include "Ecstasy," "E," "X-TC," "Adam," "clarity," "Stacy," "lover's speed," and "essence." MDMA has a chemical structure similar to both the hallucinogen mescaline and the stimulant methamphetamine (show figure 1). The drug has central stimulant and psychedelic effects that appear to be mediated by serotonin and, to a much lesser degree, dopamine [3,4].

MDMA was first synthesized in 1914 as a possible appetite suppressant. It was later used in the United States in the 1970s by a few psychotherapists as a means to facilitate insight-oriented psychotherapy sessions. More widespread illicit recreational use began to occur in the late 1980s and has continued to increase. Since the mid-1980s, MDMA has been a Drug Enforcement Administration (DEA) Schedule I drug with no accepted medical uses.

The clinical presentation and management of acute MDMA intoxication is discussed separately. (See "MDMA (ecstasy) intoxication").

• Epidemiology — The use of MDMA is a growing health concern for teenagers and young adults; its use is popular among those attending late-night "rave" parties, dance clubs, and rock concerts [1,5-7]. In addition, accidental ingestion of ecstasy has been reported in infants and toddlers [8-10].

• A study of MDMA use among college students at a single university found an increased prevalence of recreational use in 1991 compared to 1986 (24.3 versus 15.5 percent) [11].

• Surveys of university students in the United States and the United Kingdom report that 13 to 39 percent had used MDMA at least once [12,13].

• Further evidence of growing MDMA use is based on annual increases in the numbers of seized drugs submitted to DEA laboratories.

• Surveillance data from the Drug Abuse Warning Network indicate increases in mentions of MDMA in hospital emergency departments.

• Sources — MDMA usually is sold as a capsule or tablet but sometimes is found in a powder form that can be snorted or smoked. Single tablets (50 to 200 mg) are sold illicitly for 10 to 30 dollars. Descriptions of MDMA synthesis can be found in scientific journals and on the internet. The proper synthesis requires working knowledge of chemistry techniques; improper techniques are responsible for the impurities found in many preparations sold on the street. Some of the MDMA used in the United States is produced domestically; however, most MDMA is thought to be manufactured in Europe and smuggled into the United States through the use of mail and courier services.

• Pharmacology — The main effect of MDMA is on neurons that synthesize and release the neurotransmitter serotonin (5-HT). Serotonin is thought to play a role in regulating mood, appetite, and body temperature. MDMA causes serotonin release into the synaptic cleft, inhibits its synthesis, and blocks its re-uptake. The effect is an increased 5-HT concentration in the synaptic cleft and a depletion of intracellular serotonin stores [3]. The mechanism by which MDMA affects dopaminergic neurons is less well understood.

MDMA's effects begin within the first hour after ingestion of an oral dose and usually last three to six hours. Some users self-administer a "booster dose" when the effects of the initial dose wane. The effects appear to begin earlier (20 to 30 minutes) when the drug is accidentally ingested by infants and toddlers [8-10].

• Chronic use — Chronic use of MDMA in typical recreational doses can lead to a paranoid psychosis that is clinically indistinguishable from schizophrenia; usually, it is reversible after a prolonged drug-free state [14]. A considerable body of animal data and now at least one human study suggest that MDMA use (possibly in conjunction with cannabis) can lead to cognitive decline in otherwise healthy young people [15,16].

Animal studies suggest that axonal degeneration occurs in serotonergic neurons exposed to MDMA [3]. One small human study has also found, using single photon emission computed tomographic (SPECT) imaging, that heavy use of MDMA is associated with neurotoxic effects on serotonin neurons [17]. Results of the study further suggested that women may be more susceptible to neurotoxicity than men, and that the neurotoxic changes are reversible, although the sample size and methodologic problems do not permit a strong conclusion on these two points. Nevertheless, loss of serotonin neurons could result in a number of neuropsychiatric disorders in which serotonin has been implicated, including depression, anxiety and panic disorder, and disorders of impulse control.

Methamphetamine — Methamphetamine is also known as "speed," "crank," "meth," or "crystal meth," and has been produced clandestinely in the US since the 1960s (show figure 1). The dextro-form, referred to as "ice," is smoked and has a rapid onset and effects that last six to 24 hours.

Methamphetamine currently is classified as a Schedule II stimulant drug by the DEA with approval for treatment of attention deficit disorder and exogenous obesity; it is used off-label for the treatment of narcolepsy. (See "Methamphetamine"). It is included in this discussion of designer drugs because of its widespread illegal manufacture in the United States and its growing popularity among youngsters.

• A nationwide survey of youth risk behavior found that 6 percent of students had used methamphetamine in their lifetime [18].

• The 1999 Monitoring the Future survey estimated that lifetime use of methamphetamine among high school seniors increased between 1990 and 1999 (2.7 versus 4.8 percent) [19].

• Sources — Designer methamphetamine is the drug most often produced by clandestine laboratories in the United States [20]. Methamphetamine was manufactured in 1627 of the 1660 clandestine laboratories (98 percent) that were seized by the DEA in 1998 [21]. In addition, the trafficking of methamphetamine from Mexico has increased since 1992 [21].

• Contaminants — Methamphetamine that is sold on the street may be contaminated with multiple harmful byproducts, including lead and alpha-benzyl-phenylethlamine [14]. Acute lead poisoning may require chelation therapy and presents with anemia, encephalopathy, myalgias, and hepatitis [14]. (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and see "Childhood lead poisoning: Treatment").

MDA — MDA (methylenedioxyamphetamine or 3,4-methylenedioxy- amphetamine) was first synthesized in 1910 and appeared on the streets in the late 1960s (show figure 1) [22]. It is known as the "love drug" or "love pill" because of the feelings of intense euphoria and desire to be with others that it produces. MDA effects begin within an hour of ingestion and last up to six hours. MDA currently is classified as a Schedule I hallucinogen by the DEA.

MDEA — MDEA (methylenedioxyethamphetamine or 3,4-methylene- dioxyethamphetamine), also known as "Eve," is a methamphetamine analog that has pharmacologic, psychotropic, and toxic effects similar to those of MDMA, its N-ethyl analog (show figure 1). MDEA is used recreationally throughout Western Europe and in the United States as a sexual stimulant and also is popular at rave parties. It became fashionable after MDMA was restricted by the DEA.

PMA — PMA (paramethoxyamphetamine), also known as "Death," is similar to ecstasy in both clinical effects and symptoms of overdose. In one study in Australia, many patients presenting to an emergency department with reported ecstasy poisoning actually had PMA noted in urine drug screens [23]. In addition to tachycardia, hyperthermia, coma, seizures, arrhythmias, and a prolonged QT interval that can be seen with ecstasy overdose, findings unique to PMA overdose included hypoglycemia and hyperkalemia.

Clinical effects — The physiologic and psychologic effects of the various amphetamine analogs are similar; some drugs also possess mild hallucinogenic effects. These psychedelic effects are the reason that glow-in-the-dark chemical "light sticks" and laser light shows are so popular with ravers and at clubs where amphetamine analogs are used.

Users usually experience a heightened energy level; increased ability to concentrate; and feelings of euphoria, relaxation, empathy, closeness with others and enhanced sense of pleasure [24]. They may be impulsive and paranoid and may have increased risk-taking behavior.

Similar to other amphetamines, designer amphetamines suppress appetite, thirst, and the need to sleep, so much so that some users suffer from dehydration and heat exhaustion. Many users combine designer amphetamine use with "smart drinks" (drinks containing amino acid mixtures) in an attempt to maintain hydration and counteract some of the untoward effects. In some cases, however, fluid intake is markedly increased, possibly resulting in symptomatic hyponatremia [25-27]. (See "Causes of hyponatremia").

Other effects include tachycardia, hypertension, hyperthermia, tremors, and pupillary dilatation. The cardiovascular effects of MDMA (1.5 mg/kg) were documented in a double-blind, placebo-controlled trial and include increased mean heart rate (by 28 beats per minute), systolic blood pressure (by 25 mmHg), diastolic blood pressure (by 7 mmHg), and cardiac output (by 2 L per minute) [28].

The effects of MDEA (140 mg), demonstrated in a double-blind placebo-controlled crossover study, include long-lasting increases in serum cortisol, prolactin, systolic blood pressure, and heart rate, as well as increased psychomotor drive, feelings of relaxation, diminished anxiety, and depressed mood [29].

Adverse effects — Adverse effects of amphetamine analog designer drugs may be caused by host factors (eg, overexertion), impurities in the drugs, or excessive doses. In addition, the drug tablets often are mixed with other substances, including other amphetamines, ketamine, ephedrine, and LSD [30]. The relative contributions of each of these variables to amphetamine analog toxicity is not known because no controlled studies have been performed and the ingested dose usually is not known.

Life-threatening adverse effects that have been reported include hepatitis, cerebral infarction, drug-induced hyperthermia, arrhythmias, hypertensive crisis, myocardial infarction, cardiomyopathy, cardiovascular collapse, seizures, aplastic anemia, hepatotoxicity, and respiratory failure [28,31-37]. Fatalities have occurred from the above complications, from overdoses that often involve other drugs, and from accidental injuries that occur while under the influence [5,38-41].

Other reported adverse reactions include nausea, jaw clenching, bruxism, blurred vision, anxiety, agitation, obtundation, hallucinations, muscle cramping, tachycardia, hyperthermia, pneumomediastinum, excessive sweating, panic disorder, and psychosis [24,42-44].

Diagnosis — Many qualitative urine toxicology screens for drugs of abuse confirm the presence of amphetamines, methamphetamines, and their analogs. A discussion with your local laboratory regarding which amphetamine analogs they are able to detect may reveal the need for more specialized testing if designer amphetamines are suspected.

Management of intoxication — As with all symptomatic drug exposures, the initial treatment should focus on patient stabilization by ensuring an airway, breathing, and circulation.

• An intravenous catheter should be inserted, and the patient should be placed on a cardiac monitor. Vital signs, including an accurate core temperature measurement, should be monitored closely.

• Activated charcoal (1 g/kg) is effective in reducing further absorption of drug remaining in the stomach. (See "Decontamination of poisoned children", section on Activated charcoal.)

• Benzodiazepines may be useful in controlling seizures and agitation.

• Life-threatening hypertension may be treated with alpha antagonists (eg, phentolamine) or alpha and beta antagonists (eg, labetalol) or vasodilators (eg, nifedipine or nitroprusside) (See "Hypertensive emergencies: Malignant hypertension and hypertensive encephalopathy").

More specific therapy should be directed at the patient's presenting problem (eg, stroke, arrhythmia, hyperthermia). In cases of severe intoxication, methods to enhance elimination by acidification of the urine should be considered. Consultation with a clinical toxicologist is recommended.

Initial evaluation in symptomatic patients should include serum electrolytes, glucose, CBC, coagulation studies, fibrinogen, blood gas, creatinine phosphokinase, liver function tests, and an electrocardiogram. The occasional patient with symptomatic hyponatremia should be treated with water restriction and perhaps hypertonic saline.

Drug-induced hyperthermia syndrome — Amphetamine analogs have been responsible for multiple deaths since their use has become widespread [5,38,39,45]. Drug-induced hyperthermia, similar to heat stroke, is a well-documented, life-threatening complication that requires rapid recognition and treatment [40,42,46-48]. Consultation with a clinical toxicologist (available through a regional Poison Center) is strongly recommended.

• Active cooling measures should be instituted promptly (eg, iced intravenous fluids, cool water bladder washes). (See "Severe hyperthermia: Heat stroke and malignant hyperthermia", section on Management.)

• Hypotension is treated initially with isotonic fluid boluses. Ongoing hypotension can be treated with dobutamine, dopamine, and norepinephrine.

• Dantrolene (in doses ranging between 1 to 3 mg/kg) has been used to bring down the body temperature in patients with severe symptoms, though controlled trials have not been conducted [46,48,49].

• The intubation and paralyzation of patients with hyperthermia should be carefully considered as a means to decrease muscle rigidity and contractions that may contribute further to hyperthermia and the resultant rhabdomyolysis, acute renal failure, disseminated intravascular coagulation, and cerebral damage. Caution should be employed if rapid sequence intubation (RSI) is necessary. Malignant hyperthermia can be triggered by succinylcholine, a depolarizing muscle relaxant that often is used for rapid sequence intubation (RSI). Non-depolarizing muscle relaxants that are not associated with malignant hyperthermia (eg, vecuronium or rocuronium) can be used for RSI, but they have a slower onset of action.

• Measures to normalize intracranial pressure should be undertaken (eg, hyperventilation), and intracranial pressure monitoring should be considered if cerebral edema develops.

• Disseminated intravascular coagulation should be treated appropriately with platelet and FFP transfusions. (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults").

• Metabolic acidosis and hypocalcemia should be corrected.

OPIOID ANALOGS — Synthetic analogs of fentanyl and meperidine also are manufactured by "basement chemists" and are used for their heroin-like effects. These derivatives have a much higher potency than does heroin (up to a thousand times more potent) and have been responsible for deaths caused by inadvertent overdose [50]. Other health hazards relating to their use involve impurities from improper synthesis.

Fentanyl is an opiate with 100 times the potency of morphine. Its analogs can be injected, smoked, or snorted. Street names for fentanyl analogs include "Mexican brown" and "Persian white." One of the first recognized designer opioids, alpha-methyl-fentanyl, was popularly known as "China white" and appeared in California in 1980 [51]. It is estimated to be a thousand times more potent than heroin. Hundreds of fatal overdoses of "China white" and other fentanyl derivatives occurred as a result of this increased potency [50]. Three-methyl-fentanyl, another fentanyl analog with 16 times the potency of fentanyl, also has been found in street samples.

MPPP (1-methyl-4-phenyl-4-propionoxypiperidine), a heroin analog, also known as "new heroin" or "designer heroin" appeared on the streets in the early 1980s. In 1982, one batch of "new heroin" was contaminated through an error in synthesis with a by-product of MPTP and caused chronic Parkinsonism in many users [52-54]. This incident underscores the dangers of using drugs that are produced in laboratories with no controls for purity or potency.

Clinical effects — As expected, synthetic opioid effects include analgesia, euphoria, miosis, hypotension, and CNS and respiratory depression. Fatalities usually result from respiratory arrest secondary to overdose. Often the user is found with the needle still in his or her arm.

Diagnosis — Designer opioid intoxication should be suspected in any patient who presents with the signs of classic opioid toxicity but has a urine toxicology screen that is negative for opiates. Toxicology screens that detect opiates may not have the sensitivity to detect low doses of fentanyl analogs. Specialized testing for designer drugs may be indicated in cases of serious toxicity or death.

Management of intoxication — Treatment of synthetic opioid toxicity is similar to that for organic opiate toxicity. It includes supportive therapy and naloxone hydrochloride (Narcan). Supportive therapy may include intubation for airway protection and to ensure adequate oxygenation and ventilation. Blood pressure support with fluids and pressors also may be indicated. Naloxone in repeated doses (as high as 10 mg) or as a continuous infusion may be necessary to counteract the effects of opiate toxicity. (See "Opioid intoxication in children and adolescents").

ARYLHEXYLAMINE ANALOGS — Analogs of arylhexylamines, a class of drugs that includes phencyclidine (PCP) and ketamine, are manufactured and sold on the street for their psychoactive properties [14]. Ketamine is available in powder or liquid form. The powder is usually ingested orally or nasally, whereas the liquid is administered intravenously, intramuscularly, subcutaneously ("popping"), or smoked after application to cigarettes [55,56]. Phencyclidine can be taken orally or intravenously, smoked, or inhaled. (See "Overview of phencyclidine (PCP) intoxication in children and adolescents").

Clinical effects — The effects of the arylhexylamines are dose-related. The effects of low doses include inebriation, euphoria, depersonalization, nystagmus, decreased pain perception, and sympathetic stimulation [57]. At increased doses, users experience agitation, combativeness, hypertension, tachycardia, hyperthermia, and hyperreflexia. Severe intoxication can result in acidosis, rhabdomyolysis, seizures, respiratory depression, and arrest [14,55].

Diagnosis — The diagnosis of arylhexylamine intoxication should be considered in patients who present with tachycardia, hypertension, agitation, altered mental status or hallucinations, and nystagmus [56]. Arylhexylamines, particularly ketamine and the PCP analogs (PCE and TCP), may escape detection by assays designed to detect PCP. Ketamine can be detected by high-performance liquid chromatography, but this test must be specifically requested [55].

Management of intoxication — Therapy for arylhexylamine toxicity is supportive; benzodiazepines may be administered for seizures and haloperidol for combativeness. Patients with arylhexamine intoxication should be placed in a quiet place with minimal stimulation because they may experience hyperacusis. Hypertension, acidosis, and hyperthermia should be monitored and treated aggressively. Repeated doses of activated charcoal may be helpful because phencyclidine undergoes intestinal recirculation. (See "Decontamination of poisoned children", section on Activated charcoal).

METHAQUALONE ANALOGS — Methaqualone (popularly known as "quaalude") was introduced as a sleeping pill in 1965 but was reclassified as a schedule I substance in 1984. The synthesis of methaqualone is not difficult; at least two of its analogs, mecloqualone and nitromethaqualone, have been synthesized in clandestine laboratories in the United States and are sold for their psychoactive effects [58]. Toxic effects include ataxia, lethargy, obtundation, and muscle hyperactivity. Treatment of overdose is supportive.

METHCATHINONE ANALOGS — Methcathinone ("Cat") is a derivative of cathinone, a natural substance found in the leaves of the khat bush (Catha edulis), which grows in the Middle East and East Africa [59]. It is inexpensively and easily manufactured by underground chemists from its precursor, ephedrine. Methcathinone has been widely abused as a designer drug in Russia, where it is known as "Jeff." Since 1991, multiple clandestine methcathinone laboratory seizures have occurred in the northwestern, midwestern, and southern United States [59]. The drug has been classified as a schedule I substance since 1992.

Methcathinone, usually available in a powder form, can be snorted, ingested, or injected. It has amphetamine-like stimulatory effects and users report feelings of euphoria and increased sexual arousal.

Toxic effects include hallucinations, tremors, hyperreflexia, tachycardia, bradycardia, abdominal cramps, vomiting, difficulty breathing, and hypotension [59,60]. Treatment of overdose and toxicity is supportive. Routine qualitative toxicological screens often are negative in users of methcathinone [60]. However, the suspected active metabolites ephedrine and phenylpropanolamine were reportedly detected in the urine of two chronic methcathinone users [60]. Most hospital laboratories are not equipped to detect this relatively new and less commonly abused designer drug.

HERBAL DESIGNER DRUGS — A liquid product called "green hornet" is promoted on the internet and sold in stores as an herbal version of ecstasy. This product contains diphenhydramine and dextromethorphan, among other ingredients. The FDA has issued a warning to consumers not to purchase or use green hornet, or any other substances that are marketed as "safe" versions of illicit drugs. These products may cause adverse reactions including seizures, tachycardia, and hypertension [61].

Other brands of "herbal ecstasy" have different compositions, some containing caffeine and kava kava, and others ephedra [62-64]. The adverse effects of these products vary depending upon the composition but may include hypertension, tachydysrythmias, myocardial infarctions, cerebrovascular accidents, and death [62-64].

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