Psychoactive Substances of Abuse

Diana Deister

Alan D. Woolf

Sharon Levy

Misuse of drugs, chemicals, plants and herbs, mushrooms, and other agents continues to be a major cause of mortality and morbidity for adolescents and young adults (AYAs). All psychoactive substances can have toxic effects, and use may result in overdose, serious injury, or death. Chronic drug use results in long-term neurologic and other health consequences and is associated with infections (i.e., hepatitis C and sexually transmitted infections), mental health disorders, increased rates of suicide, poor functional outcomes, and underachievement. In this chapter, we review the clinical toxicology and management of the effects of psychoactive substances of abuse other than alcohol, tobacco, and marijuana. AYAs may use several drugs and chemicals concurrently, so that the consequent toxic effects may not be those classically associated with one class of substances.

COCAINE

Prevalence/Epidemiology

In 2013, 1 in 500 adolescents aged 12 to 17 were current cocaine users; the rate climbs to 1 in 90 for YAs aged 18 to 26.¹ Lifetime use of cocaine among US high school students has declined notably since the height of the “crack cocaine” epidemic in the mid-1980s; in 2014, 2.6% of high school seniors reported lifetime use of cocaine, the lowest rate since this data has been collected.² Recent cocaine initiates in 2013 were mostly (81.9%) over age 18.¹

Medical Use

Cocaine is used medically to provide local anesthesia and hemostasis (via vasoconstriction) in surgery. It is often used topically in otolaryngological, plastic surgical, and emergency medical procedures.

Preparation and Dose

Cocaine (benzoylmethylecgonine) is a stimulant made from an alkaloid contained in the leaves of the coca bush, first used by the Inca people 3,000 years ago. The cocaine commonly available is actually the hydrochloride salt, which is 89% cocaine by weight. Most cocaine is “cut” by adding an inexpensive substance with similar appearance, leading to significant variability in concentration and potency, which can result in accidental overdose. Nasal insufflation is the most common route of exposure, giving a “high” that lasts 60 to 90 minutes. Cocaine hydrochloride easily dissolves in water for injection, resulting in a faster onset but shorter duration of the high.

“Crack” is cocaine hydrochloride that has been converted to a freebase by extraction (without purification) with the use of baking soda, heat, and water. It is usually smoked with marijuana, in a tobacco cigarette or cigar, or in a crack pipe resulting in a “high” that lasts about 20 minutes. Crack cocaine can also be injected.

Physiology and Metabolism

Cocaine has many potent pharmacological actions. It is a stimulant of the central and peripheral nervous systems; it has local anesthetic activity, and it is a vasoconstrictor.

Cocaine has three different effects on the central nervous system (CNS):

Stimulation of D1 and D2 presynaptic dopamine receptors, causing the release of dopamine (primarily), serotonin, and norepinephrine into the synaptic cleft
Blockade of neurotransmitter reuptake, causing synaptic entrapment and leaving an excess of neurotransmitters in the synapse
Increase in the sensitivity of the postsynaptic receptor sites

The dopamine reuptake transporter controls the level of the neurotransmitter in the synapse by carrying dopamine back into nerve terminals. Because cocaine effectively blocks this transporter, dopamine levels remain high in the synapse, affecting adjacent neurons and perpetuating the classic “high” associated with the drug. Depletion eventually occurs as enzymes break down entrapped neurotransmitters. This leaves the user dysphoric, with feelings of irritability, restlessness, and depression when the transporter resumes normal function. The “low” can be so intense that it leads to craving and repeated use to overcome the dysphoria. The study of the neurochemical pathways underlying these neuroadaptations is facilitating new approaches to treatment, such as N-methyl-D-aspartate (NMDA) receptor antagonists that block both dopaminergic and reinforcing effects.

Cocaine also blocks neuronal reuptake of norepinephrine and stimulates release of epinephrine, leading to what has been described as an “adrenergic storm” stimulating the neurological, respiratory, and cardiovascular systems. Cocaine is similar
to methamphetamine in that both drugs achieve their reinforcing effects via profound stimulation of the mesolimbic/mesocortical dopaminergic neuronal system, which consists of the ventral tegmental area, nucleus accumbens, ventral pallidum, and medial prefrontal cortex. Repeated exposure results in either sensitization (mediated by the D1 and D2 dopamine receptors) or tolerance depending on dose and pattern of use, and causes “neuroadaptation” or progressively decreasing sensitivity of neurons, a process that explains many aspects of addiction.

Cocaine is metabolized enzymatically by hepatic esterases, and, to a lesser degree, by plasma cholinesterase to the metabolite ecgonine methylester, which is hydrolyzed nonenzymatically to form benzoylecgonine. Between 5% and 10% of cocaine is metabolized by cytochrome p450-mediated N-demethylation into norcocaine, an active metabolite with greater vasoconstrictive and neurological activity than cocaine. Progesterone increases hepatic-N-demethylation, resulting in increased formation of norcocaine, potentially increasing toxic effects in women. Increased cocaine levels occur under conditions of decreased hepatic perfusion, such as hypotension or low cardiac output. Patients with genotype-mediated, reduced enzyme activity will have decreased metabolism by plasma cholinesterase. These patients may have extreme reactions, and sudden death can occur after seemingly small doses of cocaine (Table 67.1).

Effects of Intoxication

Signs of cocaine intoxication include hyper-alert state, increased talking, restlessness, elevated temperature, tachycardia, hypertension, anorexia, nausea, vomiting, dry mouth, dilated pupils, sweating, dizziness, tremors, hyperactive reflexes.

Adverse Effects

Psychiatric/neurologic: toxic psychosis, hallucinations, delirium, formication (sense of bugs crawling on the skin), body image changes, agitation, anxiety, irritability, seizures, paresthesias, hyperactive reflexes, tremor, pinprick analgesia, facial grimaces, headache, cerebral hemorrhage, cerebral infarctions, cerebral vasculitis, coma
Skin: excoriations, rashes, secondary skin infections (Fig. 67.1)
Cardiovascular: Acute: vasoconstriction, increased myocardial oxygen demand, tachycardia, angina, arrhythmias, chest pain, aortic dissection, hypertension, stroke, myocardial infarction, and cardiovascular collapse. Dysrhythmias and conduction disturbances range from sinus tachycardia or bradycardia to bundle branch block or a Brugada pattern, to complete heart block, idioventricular rhythms, Torsades de pointes, ventricular tachycardia or fibrillation, or sudden asystole. Cocaine and metabolites (benzoylocogenine and cocaethylene) contribute to Von Willebrand Factor (VWF) release by endothelium,³ which may explain increased thrombosis. Chronic: accelerated atherosclerosis and thrombosis, endocarditis, myocarditis, cardiomyopathy, coronary artery aneurysms, bacterial endocarditis
Gastrointestinal: acute ischemia, gastro-pyloric ulcers, perforation of the small and large bowel, colitis, hepatocellular necrosis
Respiratory: Acute: pneumothorax, pneumomediastinum, pneumopericardium, pulmonary edema, “crack lung,” pulmonary hemorrhage, tracheobronchitis, and respiratory failure. Chronic: interstitial lung damage
Musculoskeletal: up to a quarter of emergency department patients with cocaine-related problems have rhabdomyolysis, which may lead to acute renal failure, disseminated intravascular coagulation, and multiorgan failure.
Obstetric: low birth weight, prematurity, microcephaly, placental abruption
Adulterant-related reactions: Levamisole, a veterinary antihelminthic agent, appeared in 69% of cocaine samples entering the US (based on 2009 Drug Enforcement Administration (DEA) estimates), and composed about 10% of each sample. Complications often seen with Levamisole are neutropenia, agranulocytosis, arthralgias, retiform purpura, and skin necrosis.³ Adulterants also include caffeine, acetaminophen, heroin, phenacetin, and many others.

Acute Overdose and Treatment

Cocaine is a short-acting drug, and treatment of cocaine overdose is similar to that for other cardiovascular and respiratory emergencies. The pathogenesis of cardiovascular complications is multifactorial and may be due not only to sympathomimetic effects but also to cocaine’s direct effects on multiple cellular targets such as cardiac potassium and calcium channels.

Initial Management

The primary response is to support respiratory and cardiovascular functions, monitor vital signs and cardiac rhythm, and establish intravenous (IV) access. Screening of both urine and blood for drugs and other substances of abuse should be done to confirm cocaine use and to check for other substances. Electrocardiographic (ECG) monitoring, cardiac isoenzymes, and a chest x-ray are other useful studies in cocaine poisoning. Blood creatine kinase, urinalysis, and renal function tests may be necessary in patients suspected of having significant rhabdomyolysis.

Removal of Residual Cocaine

All residual cocaine should be removed from the patient’s nostrils. If ingestions are suspected, or if the patient is a “body packer” or “stuffer” (see below), then activated charcoal should be administered orally or by gastric tube. If the patient presents with altered mental status, check for and treat hypoglycemia. Hyperthermia is life threatening and can be treated with antipyretics, a cooling blanket, and iced saline lavage. Muscle paralysis with a nondepolarizing agent may be necessary to reduce muscle contractions contributing to the hyperthermia. Seizures can be treated with benzodiazepines or other standard anticonvulsants. Ventricular dysrhythmias may require an antiarrhythmic agent such as lidocaine, whereas supraventricular arrhythmias may respond to therapy with calcium-channel blockers. Cardioversion may be necessary in some patients. Persistent dysrhythmias have been treated successfully in some cases with IV lipid emulsion, but its role in the routine management of patients remains unproven.⁴ Cocaine-associated chest pain should be treated with nitroglycerin, calcium-channel blockers, and aspirin. β-Blockers should be avoided unless combined with a blockade. Thrombolysis should be considered if the symptoms and signs of toxicity, an ECG, and cardiac enzymes are consistent with acute myocardial infarction. Additionally, according to recent research, medications that disrupt platelet-VWF interactions may be indicated for prevention or management of thrombotic events.⁵ Hypertensive crisis can precipitate cerebrovascular hemorrhage and must be treated emergently. Blood pressure elevations may be the result of direct CNS stimulation (treated with benzodiazepines), or peripheral a agonist effects (treated with either vasodilators (e.g., nifedipine, nitroglycerin, nitroprusside) or an α-adrenergic antagonist such as phentolamine). Agitation and psychosis may be treated with haloperidol or droperidol with consideration given to QTc prolongation from these medications and cocaine itself. To avoid further agitating acutely intoxicated patients, extraneous stimuli should be reduced. They should be approached in a subdued manner, with soft voice and slow movements. To achieve safe yet effective tranquilization in adults with agitated psychosis, the combination of intramuscular (IM) haloperidol 5 mg plus lorazepam 2 mg IM is generally well tolerated. Younger or smaller adolescents may warrant a dose reduction. Chlorpromazine should be avoided because of the possibility of a severe drop in blood pressure, provocation of arrhythmias or seizures, or anticholinergic crisis.

Flumazenil should be avoided as it may unmask seizure activity. Physical restraints should be avoided or discontinued as soon as possible due to increased risk of hyperthermia, lactic acidosis, and rhabdomyolysis.

TABLE 67.1 Physiology and Metabolism of Common Drugs of Abuse

Receptors	Pharmacodynamics	Distribution	Metabolism
Cocaine
D1 and D2 dopamine receptors	Release of dopamine, epinephrine, norepinephrine, and serotonin Blockade of neurotransmitter reuptake Increase sensitivity of postsynaptic receptor sites	Plasma and extracellular fluid	Hepatic esterases (80%) and plasma cholinesterase to form ecgonine methylester, then hydrolysis to benzoylecgonine Hepatic-N-demethylation to form norcocaine Excretion primarily in urine
Methamphetamine
Serotonin binding sites and monoaminergic reuptake sites	Release of neurotransmitters from the presynaptic neurons Direct stimulation of postsynaptic catecholamine receptors Reuptake blockade Mild monoamine oxidase inhibitor	Crosses into the CNS with CSF levels approximately 80% of plasma levels	Little metabolism Renal excretion, enhanced in acidic urine
MDMA
Serotonin 5HT2 receptors Central and peripheral catecholamine receptors	Release of serotonin into the synapse Release of endogenous catecholamines Inhibition of serotonin reuptake Depletion of serotonin stores occurs with repeated dosing, after which no further effect is achieved by taking more drug	Few pharmacologic studies have been performed in humans Peak concentrations at 2 h, half-life 8-9 h	Metabolized via cytochrome p450 isoenzyme CYP2D6 into 3,4-methylenedioxyamphetamine (MDA) 75% excreted in the urine as parent compound
Opioids
Mu, kappa, and delta opioid receptors (primarily mu)	Stimulation of opioid receptors produces euphoria, pain relief, and other effects	Morphine—low lipid solubility, crosses blood-brain barrier slowly Heroin—high lipid solubility, crosses blood-brain barrier quickly and then is metabolized, creating a “morphine rush”	Metabolized by the liver (N-demethylation, N-dealkylation, O-dealkylation, conjugation, and hydrolysis) Primarily excreted in the urine (90%)
Barbiturates
GABA-A agonists	Enhance GABA binding Open the chloride ion channel of the GABA receptor	Barbiturates bind to plasma proteins in varying amounts (50%-97%), and cross into the cerebrospinal fluid and the placenta to varying degrees	Metabolized in the liver, may enhance metabolism of other compounds Excreted by the kidney
Benzodiazepines
GABA-A receptor agonists	Enhance the binding of GABA to the GABA receptor	Protein bound Cross into the CNS based on their solubility and lipophilicity	Metabolized in the liver Many active metabolites, which account for wide variation of half-lives
LSD
Nonspecific intracellular binding throughout the CNS	Inhibition of serotonin release, resulting in: Increased firing of sensory neurons Nonspecific stress response	Primarily protein bound	Metabolized in the liver to multiple compounds; excreted by the kidney over hours (LSD) to days (metabolites).
Phencyclidine (PCP)
Glutamate-NMDA receptors	Increases the production of dopamine Inhibits dopamine reuptake	Metabolites are fat soluble, though not physiologically active	Metabolized by the liver to monopiperidine conjugate pH-dependent urinary excretion

FIGURE 67.1 Crack pipe smoker’s callus. (From Berg D, Worzala K. Atlas of adult physical diagnosis. Philadelphia, PA: Lippincott Williams & Wilkins, 2006.)

Body Stuffer Syndrome

Body stuffers hastily swallow bags of drugs while running from law enforcement officials, whereas body packers carefully seal and swallow latex gloves or condoms filled with drugs prior to border crossings, with the intent to retrieve them later. Both are at risk of drug overdose if bags leak or break (“body stuffer syndrome”), with body stuffers at greater risk. Abdominal computed tomography may be necessary to rule out residual packets prior to hospital discharge. As many as 10% of body stuffers treated with whole bowel irrigation to facilitate evacuation of bags had remaining packets after two packet-free stools; these were largely undetectable on abdominal x-ray.⁶

Chronic Use

Cocaine is irritating to the mucosa, skin, and airways, and chronic use is associated with erosion of dental enamel, gingival ulceration, keratitis, chronic rhinitis, perforated nasal septum, midline granuloma, altered olfaction, optic neuropathy, osteolytic sinusitis, rashes, burns, and local skin necrosis. People addicted to cocaine also frequently experience anorexia, weight loss, sexual dysfunction, and elevated blood prolactin levels. Cognitively, cocaine can enhance some functions in acute use, similar to methylphenidate or amphetamines; however, chronic use leads to diminished abilities in most cognitive domains, possibly due to increased atherosclerosis of brain vasculature caused by cocaine use.

Tolerance and Withdrawal

Because of cocaine’s powerful euphoric effects and short half-life, repeated use leads to rapid development of tolerance; addicts can progress from small doses to large daily quantities within weeks or months. No tolerance develops to the cardiovascular side effects. Symptoms of cocaine abstinence or withdrawal include depression, anhedonia, irritability, aches and pains, restless but protracted sleep, tremors, nausea, weakness, intense cravings for more cocaine, slow comprehension, suicidal ideation, lethargy, and hunger. There is currently no widely accepted treatment of cocaine withdrawal, and relapse rates are very high. Recent research on nonpharmacologic treatment for cocaine dependence shows that contingency management therapy—a well-established and effective treatment for adult cocaine users that consists of providing rewards for desired behaviors like clean urine tests or attending doctor’s appointments—improves outcomes in adolescents when added to standard care.⁷

Cocaethylene

When alcohol is used with cocaine, a third substance, cocaethylene, is formed in the liver. The half-life of cocaethylene is 2 hours, compared with 38 minutes for cocaine. Cocaethylene is able to block dopamine reuptake, thereby extending the period of intoxication and toxicity. When alcohol and cocaine are used together, risk of sudden cardiac death or seizures is much higher. Chronically, neurobehavioral performance suffers even after periods of abstinence.

AMPHETAMINE (AMPHETAMINE, METHAMPHETAMINE, METHYLPHENIDATE, KHAT)

Prevalence/Epidemiology

In 2013, 0.5% of Americans aged 12 or older had used stimulants nonmedically in the last 30 days.¹ “Nonmedical” use of prescription amphetamines is increasingly common among youth, and ranges from taking someone else’s prescription while studying to clear abuse and “getting high.” The average age of first-time users of methamphetamine was 18.9 years in 2013,¹ indicating that prevention efforts must be made in early to mid-high school. From 2005 to 2010, emergency department visits in the US due to prescription stimulant use increased nearly three-fold, driven by dramatic increases in adult age-groups (especially for 18- to 25-year-olds) for both nonmedical use and adverse reactions, with no change in rates for adolescents. This may be due in part to greater cardiovascular risk at older ages.⁸

Medical Use

Amphetamines are used to treat attention-deficit/hyperactivity disorder and narcolepsy, and as a weight loss aid. Despite its potential for misuse, appropriate stimulant treatment does not appear to increase the risk of developing a substance use disorder (SUD). Longer-acting medications may have lower addiction potential than short-acting ones; once-daily dosing also facilitates easier supervision and pill counts by parents.

Preparation and Dose

The term “amphetamine” refers to a class of drugs containing an amphetamine base, available either in prescription form (such as amphetamine, dextroamphetamine, lisdexamfetamine), or illicitly manufactured (mainly in the form of methamphetamine). Amphetamines are CNS stimulants. Methamphetamine has a stronger effect on the CNS than other forms of amphetamine. Methylphenidate (and its enantiomer dexmethylphenidate) is a non-amphetamine stimulant with similar actions available in prescription form.

Amphetamine and methamphetamine differ structurally by the addition of one methyl group. Methamphetamine can be easily produced in clandestine “labs,” beginning with ephedrine or pseudoephedrine found in over-the-counter medications, though availability of these precursors was limited by US federal law in 2005. Synthesis involves heating volatile solvents, which may often lead to explosions and fires. Meth labs are considered to be toxic waste sites that may be explosive; in the US, most are in residential areas, putting local residents at risk both during and after production. Illicitly synthesized methamphetamine may be contaminated by organic or inorganic impurities such as heavy metals (e.g., lead, mercury), solvents, and carcinogens. In recent years, the inexpensive and portable “shake and bake” method of methamphetamine production, which requires no lab equipment but can still be explosive, has gained popularity, leading to injuries, burns, and death.

The D-isomer (D-methamphetamine) is cortically more active than the L-isomer (the active ingredient in Vicks Inhaler). Water-soluble methamphetamine HCl is much more versatile than the hydrochloride salt of cocaine. It has high bioavailability in the salt form by any route of administration, such as snorting, smoking,
ingesting by mouth, or passing across other mucous membranes such as the vaginal mucosa. “Ice” consists of pure crystals of D-methamphetamine.

Street methamphetamine may be mixed with many drugs, including cocaine. Studies show that 8% to 20% of street-available stimulants contain both drugs. Look-alikes containing combinations of caffeine, ephedrine, and phenylpropanolamine are particularly dangerous. A much larger dose of this combination is necessary to achieve the same level of cortical stimulation achieved with amphetamines. This combination also has greater cardiovascular stimulation, so abuse of look-alikes puts the user at great risk for stroke, myocardial infarction, or hypertensive crisis.

Prescription amphetamines are typically ingested orally or via nasal insufflation; illicit methamphetamine is usually smoked. Either preparation may be ground up, heated, and injected intravenously. Smoking methamphetamine may be more potent and addictive than snorting or ingesting it; smoking produces higher concentrations of drug in the brain for a shorter period.

Physiology and Metabolism

Amphetamines are CNS stimulants that work as sympathomimetic drugs. Amphetamines release neurotransmitters from presynaptic neurons, stimulate postsynaptic catecholamine receptors, prevent reuptake of neurotransmitters (dopamine, serotonin, and norepinephrine), and mildly inhibit the enzyme monoamine oxidase. Stimulation of the nucleus accumbens causes the experience of pleasure. Stimulation of the basal ganglia causes repetitive movements that may be seen in patients with amphetamine addiction. Increased serotonin levels are associated with changes in sleep and appetite patterns, increased body temperature, mood changes, aggressiveness, and psychosis.

Effects of Intoxication

As with cocaine, users experience increased energy, psychological euphoria, and physical well-being, but effects last much longer (12 hours versus 1 hour for cocaine).

Symptoms of amphetamine intoxication include hyperalertness, anxiety, confusion, irritability, aggression, delirium, dry mouth, tachycardia, hypertension, tachypnea, jaw clenching, bruxism (teeth grinding), reduced appetite, sweating, and psychosis. Amphetamine related deaths may arise from direct physiologic effects (myocardial infarction, cerebrovascular complications, seizures, maternal-fetal and infant exposures) or mental and behavioral impairments (assaults, suicides, homicides, accidents, driving impairment).

Adverse Effects

Psychiatric/Neurological: aggressiveness, confusion, delirium, psychosis, post-use dysphoria, seizures, choreoathetoid movements, cerebrovascular accidents, cerebral edema, cerebral vasculitis, hyperthermia
Cardiovascular: tachycardia, hypertension, atrial and ventricular arrhythmias, myocardial infarction, cardiac ischemia, coronary artery vasospasm, necrotizing angiitis, arterial aneurysms, aortic dissections. Li et al.⁹ demonstrated in rats that cardiovascular collapse occurs due to concentration of methamphetamine in the brain stem nuclei responsible for regulation of respiration and circulation, leading to cell death by oxidative damage.
Gastrointestinal: ulcers, ischemic colitis, hepatocellular damage
Musculoskeletal: muscle contractions, tremors, rhabdomyolysis
Respiratory: pneumomediastinum, pneumothorax, pneumopericardium; acute noncardiogenic pulmonary edema, pulmonary hypertension
Renal: acute tubular necrosis, acute renal failure due to rhabdomyolysis
Dental: chronic gingivitis, numerous dental caries, severe dental abscesses and necrosis (known colloquially as “meth mouth”) (Fig. 67.2)

FIGURE 67.2 Dental changes such as blackened, stained, rotting teeth and tooth loss, referred to collectively as “meth mouth,” are the result of abusing methamphetamine. (Photo by Dozenist, University of Tennessee Health Science Center, College of Dentistry, Memphis, Tennessee. In: Timby BK, Smith NE, eds. Introductory medical-surgical nursing. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2013.)

Overdose and Emergency Treatment

Complications of amphetamine overdose resemble those of cocaine, although amphetamines do not affect nerve conduction as cocaine does. As with cocaine, emergency treatment is directed toward cardiovascular and respiratory stabilization and control of seizures. Agitation on presentation (39%), suicidal ideation (31%), and suicide attempt (21%) are commonly seen in methamphetamine poisonings in teens (age 11 to 18); suicidality was significantly higher than a control cohort, indicating the need for assessment for suicidal ideation after stabilization.¹⁰ Patients who present to emergency departments for acute intoxication may require pharmacological intervention for agitation; multiple trials have shown effectiveness of antipsychotics (haloperidol, droperidol, risperidone, aripiprazole, quetiapine) and/or benzodiazepines (diazepam, lorazepam), though haloperidol should be used with caution as coadministration of methamphetamine and haloperidol caused excitotoxicity and cell death in the substantia nigra pars reticula in a rat model.¹¹ Avoid chlorpromazine (Thorazine), which can cause hypotension, anticholinergic crisis, or seizures.

Chronic Use

Chronic use of amphetamines can produce severe psychiatric as well as physical problems, including loss of executive function, delusions, hallucinations, long-term personality changes, and formication, leading individuals to tear and damage their skin. Choreoathetoid movements and other movement disorders are common and may persist after cessation of drug use. Chronic use of amphetamines or cocaine is associated with loss of gray matter volume in the frontal cortex.

Tolerance and Withdrawal

Tolerance to methamphetamine causes users to frequently escalate dose or change the route of administration to maintain the desired effect. Symptoms of withdrawal include irritability, agitation, depression, fatigue, sleep problems, increased appetite, headaches, and drug cravings; these symptoms may begin as soon as the high ends, can last up to 7 to 10 days, and are treated supportively.

STP

STP (2,5-dimethoxy-4-methylamphetamine, also known as DOM or the “serenity-tranquility-peace pill”), is a substituted amphetamine with selective serotonin (5-HT_2A, 5-HT_2B, and 5-HT_2C) partial agonist properties. Its powerful psychedelic, hallucinogenic
properties are mediated by its 5-HT_2A agonist activity. Its effects are also similar to those of other hallucinogenic drugs, with the exception that with STP the incidence of unpleasant sensations is increased, and the effects seem to last longer, up to 72 hours.

Cathinone (Khat) and Cathine, “Bath Salts,” “Plant Food”

Cathinone is chemically similar to D-amphetamine, and cathine (D-norisoephedrine) is a form of cathinone with less psychoactive effect. These compounds are the active ingredients in khat leaves (Catha edulis), which are used as a tea or chewed for their euphoriant and stimulant effects by persons in Africa, the Middle East, and corresponding immigrant and refugee communities in developed nations. Outside of the US, khat is used within cultural norms with little evidence of abuse. Recently, synthetic cathinones have been marketed with names such as “bath salts” and “plant food.” “Bath salt” use rates have been tracked since 2012 and remain low for high school students (about 1%) and lower for young adults aged 19 to 28 (0.4%).²,¹²

The most common synthetic compounds are 3,4-methylenedioxypyrovalerone, mephedrone, and methylone. While classified by the DEA as schedule I drugs, many chemical variants with similar properties are still legally marketed. These drugs are inexpensive to manufacture and easy to market on store shelves (in volumes of 200 mg to 10 g) and are often labeled as “not for human consumption.” They are typically available as white or yellow powders (or rarely in pill form) and can either be ingested orally or through nasal insufflation. Banning the entire category is not feasible because other members are used medically as antidepressants or anorexiants.¹³

Effects of intoxication are similar to those for cocaine, methamphetamine, and methylene dioxymethamphetamine (MDMA); adverse reactions may be severe, including excited delirium and psychosis. Khat-induced psychosis most commonly occurs in the context of nonculturally sanctioned polydrug abuse. Khat and synthetic cathinones have been associated with multisystem organ failure: cardiac, gastrointestinal, neurologic, and psychiatric.¹⁴

ECSTASY/MDMA/MOLLY (METHYLENE DIOXYMETHAMPHETAMINE)

Prevalence/Epidemiology

According to the 2013 National Survey on Drug Use and Health, lifetime prevalence rates for MDMA use for teens aged 12 to 17 years and young adults aged 18 to 25 years were 1.5% and 12.8%, respectively.¹ Recently, MDMA has been rebranded as “Molly” (short for molecule) and advertised as “purer” and therefore “safer” than Ecstasy, although both are of highly variable content (varying from 0% to 100% MDMA).

Medical Use

MDMA was first patented in 1912 as an appetite suppressant; however, it was never manufactured or sold commercially and it has no current medical uses. MDMA continues to be studied as an adjunct to psychotherapy for conditions such as posttraumatic stress disorder (PTSD), with unconvincing results.

Preparation and Dose

The majority of pharmaceutical-grade MDMA tablets are now produced in Europe and smuggled into the US. The drug is sold as a tablet or capsule, often with a symbol printed on it. Tablets sold as MDMA may actually contain MDA, MDEA, or something entirely unrelated to the drug, such as LSD, caffeine, pseudoephedrine, or dextromethorphan. Orally ingested doses take approximately 30 to 60 minutes for onset of effect and the duration of action is 3 to 6 hours. Many users begin with a low dose (40 to 70 mg) and gradually add more pills until they experience the desired effect at a common dosage range of 75 to 125 mg, a practice known as “rolling.” MDMA can be snorted, smoked, or injected, but is usually taken orally.

Physiology and Metabolism

MDMA binds to the serotonin transporter in vesicles and the plasma membrane and stimulates release of serotonin into the synapse where excess serotonin binding to postsynaptic receptors results in its effects. Serotonin has a variety of neurotransmitter actions, including control of wakefulness, appetite and satiety, regulation of mood and emotional states, and thermoregulation and circadian rhythms. Serotonin also causes release of oxytocin and vasopressin, both of which have roles in sexual arousal as well as such emotions as love and trust. Serotonin is largely broken down in the synapse by monoamine oxidase; repeated use of MDMA causes serotonin depletion, after which further doses have little or no effect. Single doses of MDMA have caused nerve damage in animal studies.

Effects of Intoxication

MDMA has both stimulant and hallucinogenic effects. Users describe feelings of enhanced well-being and introspection, empathy, love, affection, and increased energy.

Adverse Effects

Psychiatric/neurologic: confusion, depression, fatigue, sleep problems, anxiety, seizures, paranoia, spasms, bruxism, hyperthermia, sweating, syndrome of inappropriate antidiuretic hormone (SIADH), blurred vision, faintness, chills, excessive sweating, hyponatremia, hyponatremic dehydration, serotonin syndrome (with repeated dosing, or when taken with selective serotonin reuptake inhibitors [SSRIs])
Musculoskeletal: muscle rigidity, rhabdomyolysis
Cardiovascular: tachycardia, hypertension, arrhythmias, cardiovascular failure, asystole
Gastrointestinal: nausea, severe hepatic damage requiring transplantation.⁸ MDMA enhances hepatic damage of alcohol by inhibiting aldehyde dehydrogenase 2, resulting in accumulation of toxic acetaldehyde (similarly to disulfiram).¹⁵
Developmental: infants of mothers who used MDMA regularly during the first trimester showed gross psychomotor retardation both at 4 and 12 months of age.¹⁶

Overdose and Emergency Treatment

The most common reaction to MDMA overdose is a syndrome of altered mental status, tachycardia, tachypnea, flushed appearance, profuse sweating, and hyperthermia; this syndrome is similar to the sympathomimetic effects of acute amphetamine overdose. MDMA should be suspected if a routine urine screen for amphetamines is negative. Serious complications such as delirium, seizures, and profound coma are more frequent with the combination of MDMA and other substances. AYAs who present late at night on weekends and have clinical manifestations of sympathetic overactivity and increased temperature (“Saturday night fever”) should be suspected of using stimulants, and MDMA in particular. Patients chronically taking serotonin reuptake inhibitors or MAO inhibitors for depression risk fatal drug interactions when they ingest MDMA.

Treatment of toxic ingestions of MDMA is supportive, including support of airway, breathing, and circulation; assessment and treatment of cardiac arrhythmias; and monitoring of vital signs and level of consciousness. Close monitoring of serum electrolytes and fluid balance is required to detect the SIADH and/or water loading-induced hyponatremia. Hyperthermia should be treated with cooling blankets and IV fluids; muscle relaxants, anticonvulsants, and sedatives may be indicated. MDMA can be lethal due to hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, renal failure, cardiac arrhythmias and sudden asystole, hyponatremia, seizures, serotonin syndrome, hepatic failure, cerebral infarction, and cerebral hemorrhage.

Chronic Use

Chronic MDMA use is associated with long-term cognitive impairments in retrospective memory, prospective memory, higher cognition, problem solving, and social intelligence.¹⁷ Impairments in sleep, vision, and cortisol metabolism (with cortisol levels 800% above baseline during MDMA use) have been well documented. Long-lasting impairment of the 5-hydroxytryptamine (5-HT) system has been found in past users of MDMA, which may be more prominent in females and may be reversible in some patients. In rats, use of caffeine with MDMA or MDA enhances hyperthermic effects acutely and serotonergic loss in the long term.¹⁸

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