76: Amphetamines

Amphetamine is the acronym for racemic β-phenylisopropylamine or α-methylphenylethylamine. Amphetamine is representative of a broader group of compounds with a shared structure known as phenylethylamines, which is a more precise term. Numerous substitutions are possible on the phenylethylamine structure, resulting in a variety of compounds, some with unique properties. For the purposes of this chapter, all phenylethylamines that are not actually amphetamine will be called amphetamines, and the name amphetamine specifically refers to β-phenylisopropylamine.

Amphetamine was first synthesized in 1887, but was essentially lost until the 1920s, when there were concerns about the supply of ephedrine for asthma therapy.⁷¹ The attempt to synthesize ephedrine lead to the rediscovery of dextroamphetamine in the United States and methamphetamine (d-phenylisopropylmethylamine hydrochloride) in Japan.⁷¹ Amphetamine was first marketed by Smith, Kline, and French in 1932 as the nasal decongestant Benzedrine.¹⁵ Amphetamine tablets were later available in 1935 for the treatment of narcolepsy and were advocated as anorectants in 1938.⁷⁶

Both amphetamine and methamphetamine were supplied as stimulants for soldiers and prisoners of war in World War II. The stimulant and euphoric effects of amphetamine were recognized, with abuse reported as early as 1936.¹³⁷ As a result, Benzedrine inhalers were banned by the US Food and Drug Administration (FDA) in 1959. From 1950 to the 1970s, there were sporadic periods of widespread amphetamine use and abuse in the United States. In the 1960s, various amphetamines such as methylenedioxyamphetamine (MDA), para-methoxyamphetamine (PMA), and para-methoxymethamphetamine (PMMA) were popularized as hallucinogens.³⁴ The Controlled Substance Act of 1970 placed amphetamines in Schedule II to prevent the diversion of pharmaceutical amphetamines for nonmedicinal uses.⁵ Amphetamine abuse subsequently declined.⁹³

In the 1980s, use of methylenedioxy derivatives of amphetamine and methamphetamine surfaced and were able to circumvent existing regulations. The best known of these derivatives were 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethamphetamine (MDEA).⁴⁶ Since the late 1980s, a dramatic resurgence of methamphetamine abuse has spread throughout much of the United States. A high purity preparation of methamphetamine hydrochloride was marketed in a large crystalline form termed “ice” by abusers.^7,49 From 1991 to 1994, the number of methamphetamine-related deaths in the United States reported by medical examiners tripled from 151 to 433, with a disproportional distribution from the Los Angeles, San Diego, San Francisco, and Phoenix metropolitan areas. Methamphetamine use is particularly prevalent among men who have sex with men in New York City.⁷⁴ Because of the ease and low cost of methamphetamine synthesis and the local production, methamphetamine is the most common illicit drug produced by clandestine laboratories in the United States.^28,31 Since the mid-1990s, MDMA has become widely used by college students and teenagers in large gatherings, known as “rave” or “techno” parties in England, Australia, and the United States.^135,136 Methcathinone (a khat-derived substance) use in the midwestern United States and 4-bromo-2,5-methoxyphenylethylamine (2CB) use in dance clubs were popular in the 1990s, but the use was not widespread.^63,67,180 Recently, synthetic cathinones have resulted in serious toxicity and death³⁰; these drugs have been sold as “bath salts” or “legal highs” to circumvent existing laws. There are also older amphetamines such as PMA and PMMA that have made a resurgence, with recent reports of toxicity and deaths.

The pharmacologic effects of amphetamines are complex, but their primary mechanism of action is the release of catecholamines, particularly dopamine, norepinephrine, and serotonin from the presynaptic terminals, leading to a hyperadrenergic state. Although there are conflicting mechanistic models of amphetamine induction of catecholamine release, these variable results may be directly correlated with the different concentrations of amphetamine used in experimental models. The mechanism of action of amphetamines are based on dopaminergic neurons; similar mechanisms occur with norepinephrine and serotonin. Two storage pools exist for dopamine in the presynaptic terminals: the vesicular pool and the cytoplasmic pool. The vesicular storage of dopamine and other biogenic amines is maintained by the acidic environment within the vesicles and the persistence of a stabilizing electrical gradient within the cytoplasm. This environment is maintained by an adenosine triphosphate (ATP)-dependent active proton transport system.^117,147

Amphetamines will enter the nerve cell either by passive diffusion or by exchange diffusion through a reuptake transporter that is partially dose dependent. At low concentrations, amphetamines release dopamine from the cytoplasmic pool by exchange diffusion at the dopamine reuptake transporter site in the membrane. At moderate concentrations, amphetamines diffuse through the presynaptic terminal membrane and interact with the neurotransmitter transporter on the vesicular membrane to cause exchange release of dopamine into the cytoplasm. Dopamine is subsequently released into the synapse by reverse transport at the dopamine reuptake site.^147,161 At high concentrations, an additional mechanism is invoked as amphetamines diffuse through the cellular and vesicular membranes. Because amphetamine are bases, they alkalinize the vesicles, permitting dopamine release from the vesicles and delivery into the synapse by reverse transport (Fig. 76–1).^161,162 Amphetamines may also block the reuptake of catecholamines by competitive inhibition.^72,177 However, the effects of this mechanism are considered minor. Amphetamines are structurally similar to amphetamine derived monoamine oxidase inhibitors such as tranylcypromine, so amphetamines are weak monoamine oxidase inhibitors, the clinical significance of which is unclear.¹³¹

Binding selectivity to the neurotransmitter transporters largely determines the range of pharmacologic effects for the particular amphetamine. The affinity of MDMA for serotonin transporters is 10 times greater than that for dopamine and norepinephrine transporters; hence, it produces primarily serotonergic effects.⁶⁸ There are also other amphetamines that are predominantly serotonergic such as paramethoxyamphetamine and BromodragonFLY (Table 76–1).

The most identifiable effects of amphetamines are those caused by excessive catecholamine release and the resultant stimulation of many receptors that include α-adrenergic receptors, β-adrenergic receptors, dopamine, and serotonin. The majority of the serotonergic neurons in the central nervous system (CNS) are located in the raphe nuclei. Serotonin within the CNS regulate a wide variety of functions, including, but not limited to, mood, memory, temperature regulation, sleep, and pain.⁷¹ Serotonin is primarily responsible for the hallucinogenic and illusionic properties of amphetamines. Serotonin is also involved with the release of antidiuretic hormone, which may lead to hyponatremia, particularly with amphetamines with potent serotonergic effects such as MDMA.⁷⁵ Serotonin is also concerned with regulating fluid secretion and peristalsis. In addition, serotonin is involved in the regulation of many vascular beds, although the role of amphetamines in the regulation of the peripheral effects of serotonin is not clear.

Norepinephrine is another important neurotransmitter involved with amphetamines. Norepinephrine is found in the CNS and is also released from the postganglionic sympathetic fibers. The main noradrenergic nucleus in the CNS is the locus ceruleus. The release of excessive norepinephrine within the CNS from amphetamines results in decreased fatigue and increased attentiveness. Excessive norepinephrine in the peripheral nervous systems leads to many of the findings that occur with other sympathomimetic drugs such as cocaine. Norepinephrine will act on the adrenergic receptors (α and β), which mediate vasoconstriction and increased cardiac activity resulting in hypertension and tachycardia.

Dopamine also plays an important role in the setting of amphetamine use. The increase in CNS dopamine, particularly in the neostriatum, mediates stereotypical behavior and other locomotor activities.^39,65,89,90 The activity of dopamine in the neostriatum appears to be linked to glutamate release and inhibition of γ-aminobutyric acid (GABA) ergic efferent neurons.^65,90 Stimulation of the glutamatergic system contributes significantly to the stereotypical behavior, locomotor activity, and neurotoxicity of amphetamines.^90,153,154 The effects of serotonin and dopamine on the mesolimbic system alter perception, cause psychotic behavior and anorexia.^78,160

Structure Modification

A phenylethylamine is any structure with an ethyl group backbone that has an aromatic group and a terminal amine. Specific substitutions made to the phenylethylamine backbone have led to the wide variety of novel drugs, described below. Substitutions at different positions of the phenylethylamine molecule alter the general pharmacology and clinical effects of amphetamines, as demonstrated by both animal and human observations. Large-group substitution at the α carbon reduces the stimulant and cardiovascular effects but retains the anorectic properties (such as phentermine). Substitution at the para position of the phenyl ring enhances the hallucinogenic or serotonergic effects of amphetamines (such as in para-chloroamphetamine and MDMA).⁴⁹ Although some of these generalizations enable an understanding of the effects of amphetamines, there are many exceptions, and such generalizations may not apply when large doses of a particular molecule are ingested. In terms of the spectrum of activities, methamphetamine results in the most potent cardiovascular effects, and 2,5-dimethoxy-4-bromoamphetamine (DOB) results in the most consequential hallucinogenic and serotonergic effects.¹⁰⁵ Table 76–2 further describes the pharmacology of specific substitutions.

Other certain substitutions are worth noting, such as the addition of an extra methyl group to the terminal amine in amphetamine to produce methamphetamine that greatly increases CNS activity. This extra methyl group also makes methamphetamine more lipid soluble, allowing faster penetration across the blood–brain barrier and more resistance to degradation by monoamine oxidase. In addition, amphetamines with this methyl group also possess strong stimulant, cardiovascular, and anorectic properties.¹⁰⁵ Addition of a methoxy group to either the 2 or 5 position of the aromatic ring on the amphetamine or methamphetamine compound increases serotonergic activity. Another important substitution to the phenylethylamine backbone is the addition of a halogen group (such as iodine or bromide), which increases the potency of the compound and leads to it being considered more neurotoxic when compared to nonhalogenated compounds. This is thought to be due to significant serotonin depletion leading to irreversible neuron damage.

Because amphetamines directly interact with neurotransmitter transporters, minor modifications of the molecule may significantly alter its pharmacologic profile.⁸² The addition of an α-methyl group in amphetamines confers resistance to metabolism by monoamine oxidase. These characteristics permit better oral bioavailability and longer duration of effect. The α-methyl group in the amphetamine structure also introduces chirality to the molecule. Except for MDMA and several other amphetamines, the d-enantiomers are typically 4 to 10 times more potent than the l forms of amphetamine.

Chronic administration of certain amphetamines to animals alters dopamine and serotonin transporter functions, depletes dopamine and serotonin in the neuronal synapses, and produces irreversible destruction of those neurons.^{14,60,141,142,147,176} The etiology of neuronal toxicity may be related to the generation of oxygen free radicals, resulting in the generation of toxic dopamine and serotonin metabolites as well as neuronal destruction. Based on animal models, dose, frequency and duration of exposure, and ambient temperature. Intact dopamine or serotonin transporters are necessary to produce neurologic injury. Xenobiotics that inhibit transporter function may prevent neurologic injuries in animals.⁶⁸ Significant differences are also noted across species; mice are typically resistant to MDMA-induced neurologic injury. Although not as well studied as MDMA, studies of former methamphetamine users demonstrated impaired memory and psychomotor functions, as well as corresponding dopamine transporter dysfunction and abnormal glucose metabolism on positron emission tomography scans. However, it is still not clear as to the difference in species susceptibility to neurologic injuries, the duration of effects in primates and humans, and functional consequences of neurotoxicity in humans. The potential for permanent neurologic effects associated with chronic amphetamine use in humans requires further study.

Absorption

Amphetamines can be administrated intravenously, orally, intranasally, and by inhalational route, with good absorption. All amphetamines are rapidly absorbed, with bioavailability that ranges between 60% and 90% depending on the route of administration. Peak serum concentrations are achieved in approximately 3 to 6 hours postadministration.

Distribution

Following absorption, amphetamines are distributed to most compartments of the body. Most amphetamines are also relatively lipophilic and readily cross the blood–brain barrier. Amphetamines have large volumes of distribution, varying from 3 to 5 L/kg for amphetamine, 3 to 4 L/kg for methamphetamine and phentermine, and to 11 to 33 L/kg for methylphenidate. Some amphetamines such as pemoline have a small volume of distribution (0.2–0.6 L/kg).

Metabolism

Amphetamines are eliminated via multiple pathways, including diverse routes of hepatic transformations, and by renal elimination. For MDMA and its analogs, N-dealkylation, hydroxylation, and demethylation are the dominant hepatic pathways. Depending on the particular amphetamines, active metabolites of amphetamines and ephedrine derivatives may be formed. N-demethylation of methamphetamine and MDMA result in the formation of amphetamine and MDA, respectively.^33,111 Dealkylation and demethylation are mainly performed by CYP1A2, CYP2D6, and CYP3A4, but they are also performed by flavin monooxygenase. Polymorphism of CYP2D6 in humans was recognized due to the diversity of rates of p-hydroxylation of amphetamines. Since its discovery, CYP2D6 polymorphism has been implicated in drug toxicity, substance use and abuse, and lack of drug efficacy in selected individuals.¹⁴⁸ Increased amphetamine toxicity is a potential concern in patients with decreased CYP2D6 activity. Although animals with CYP2D6 deficiency are more susceptible to MDMA toxicity, limited studies in humans do not demonstrate an association between mortality and CYP2D6 polymorphism.^59,122 In general, because multiple enzymes and pathways (including renal) are involved in amphetamine metabolism, it is less likely that CYP2D6 polymorphism or drug interactions with CYP3A4 alone will significantly increase toxicity. However, it is unclear if toxicity is enhanced when multiple mechanisms for altering drug metabolism and kidney dysfunction are present simultaneously.

Elimination

Renal elimination of the parent compound is substantial for amphetamine (30%), methamphetamine (40%–50%), MDMA (65%), and phentermine (80%). Amphetamines are bases with a typical pK_a range of 9 to 10, and renal elimination varies depending on the urine pH, with elimination increasing as pH decreases. The half-life of amphetamines varies significantly: amphetamine, 8 to 30 hours; methamphetamine, 12 to 34 hours; MDMA, 5 to 10 hours; methylphenidate, 2.5 to 4 hours; and phentermine, 19 to 24 hours. Repetitive administration, which occurs typically during binge use, may lead to drug accumulation and prolongation of the apparent half-life and duration of effect.⁷⁷

Acute Toxicity

Most of the complications associated with amphetamines are a result of an uncontrolled hyperadrenergic state similar to what occurs with other sympathomimetics such as cocaine, except the duration of effect may be longer (Table 76–3). Most patients with acute amphetamine toxicity manifest effects in the CNS and cardiovascular system. The majority of the specific effects are from excessive catecholamine release as opposed to direct effects from the amphetamines themselves. Refer to the section Individual Amphetamines for specific effects.

Central nervous system effects from acute amphetamine use include anxiety, agitation, hallucinations, mydriasis, diaphoresis, and hyperthermia.^19,50,51,145 Psychosis appears to be a more prominent feature than following cocaine use.⁶⁵ Intracerebral hemorrhage and cerebral infarction are also reported with amphetamine use.^{53,86,113,129} Seizures may be the direct result of amphetamine use or may occur secondarily from hyponatremia as reported with MDMA and certain synthetic cathinones.¹⁸

Cardiovascular toxicity from acute amphetamine use involves hypertension, tachycardia, and dysrhythmias; this varies from premature ventricular complexes to ventricular tachycardia and ventricular fibrillation.⁸⁰ Other vascular complications reported with acute use include myocardial ischemia or infarction,^115,169 aortic dissection,^52,172 acute respiratory distress syndrome,^165,171 obstetrical complications, fetal death,¹⁰⁴ and ischemic colitis.^79,84 Other complications are metabolic acidosis, rhabdomyolysis,⁵⁴ acute kidney injury (acute tubular necrosis), and coagulopathy, often from uncontrolled agitation and hyperthermia^43,73,167 (Fig. 5–29). Unless these systemic signs and symptoms are rapidly reversed, multiorgan failure and death may ensue.

Chronic Toxicity

Amphetamine users seeking intense “highs” may go on “speed runs” for days to weeks. Because of the development of tolerance, they use increasing amounts of amphetamine during these periods, usually without much nutritional sustenance or sleep, while attempting to achieve their desired euphoria.¹⁵¹ Acute psychosis resembling paranoid schizophrenia may occur during these binges and has contributed to both amphetamine-related suicides and homicides.⁵⁵ Return to a normal sensorium occurs within a few days after discontinuation of the drug. Once an amphetamine user experiences psychosis, it is likely to recur with subsequent use, even after prolonged abstinence, which may be related to a kindling phenomenon.¹¹⁴ Typically, after such binges, patients may sleep for prolonged periods of time, feel hungry and depressed when awake, and often have amphetamine cravings.^95,99

Compulsive repetitive behavior patterns from the use of amphetamines are reported in humans and animals. Individuals may constantly pick at their skin; grind their teeth (bruxism); or perform repetitive tasks, such as constantly cleaning the house or car. MDMA users often carry pacifiers to relieve bruxism. Choreoathetoid movements, although uncommon, are reported with acute and chronic amphetamine usage.^94,106,110 The etiology of the choreoathetoid movements may be related to increased dopaminergic stimulation in the striatal area.

Necrotizing vasculitis is associated with amphetamine abuse. Angiography typically demonstrates beading and narrowing of the small- and medium-sized arteries (Fig. 5–29). Progressive necrotizing arteritis can involve multiple organ systems, including the brain, heart, gut, and kidney.^{17,35,98,110,164} Complications include cerebral infarction and hemorrhage, coronary artery disease, pancreatitis, and acute kidney injury. The etiology of the arteritis remains unclear. Although various contaminants associated with injection drug use are postulated as potential etiologies, in animal models oral and intravenous amphetamine administration is also associated with vasculitis, suggesting that this is a direct amphetamine effect. Cardiomyopathy is also reported with acute and chronic amphetamine abuse.^157,178 Excessive catecholamine exposure may be responsible for their associated cardiomyopathies similar to patients with pheochromocytomas and chronic cocaine use.^88,173 Other reported effects include valvular disease and pulmonary hypertension with certain amphetamines used as dieting agents such as fenfluramine, dexfenfluramine, and phentermine.^146,163

Finally, complications can result from intravenous drug use and from the associated contaminants. Contamination with microbials may lead to human immunodeficiency virus infection, hepatitis, and malaria. Bacterial and foreign body contamination may result in endocarditis, tetanus, wound botulism, osteomyelitis, and pulmonary and soft tissue abscesses.³⁴

The choice and extent of diagnostic tests should be guided by the history and physical examination. In all patients with altered mental status, blood specimens should be sent for glucose, blood urea nitrogen, and electrolyte assays. An electrocardiogram should be obtained in all cases, and continuous cardiac monitoring should be initiated. A complete blood count, urinalysis, coagulation profile, creatine phosphokinase, chest radiograph, computed tomography scan of the head, and lumbar puncture may be necessary, depending on the clinical presentation.

Qualitative urine immunoassays are available for amphetamines, but several considerations limit their utility in the management of acutely poisoned patients. While point of care urine tests are available, the turnaround time for many urine immunoassays is at least several hours so they rarely contribute to management in the acute setting. Another important limitation to consider is the rate of false-positive and false-negative results that are common with the amphetamine immunoassay. For example, many cold preparations contain pseudoephedrine, which is structurally similar and may cross-react with the immunoassay.^36,41,57,132 Likewise, selegiline, a selective monoamine oxidase type B inhibitor used for the treatment of parkinsonism, is metabolized to amphetamine and methamphetamine. Other common drugs that produce false-positive outcomes include bupropion, trazodone, and amantadine.^120,124 Even a true-positive result only means the patient has used certain amphetamines within the past several days and does not distinguish remote from acute use. False-negative results may occur with certain amphetamines such as MDMA and cathinones, which are not recognized on standard urinary drug testing.^36,156 Although newer, rapid, serum qualitative drug screens are available, false-positive and false-negative results remain common and may be misleading and do not directly contribute to the acute management of patients. The gold standard for drug testing, gas chromatography–mass spectrometry analysis, can misidentify isomeric substances such as l-methamphetamine, which is present in nasal inhalers, with d-methamphetamine, if performed by inexperienced personnel.⁹⁶ In summary, the use of urine immunoassays should not guide clinical management of patients who present with suspected toxicity from amphetamines.

The initial medical assessment of the agitated patient must include vital signs, a rapid glucose and a complete physical examination. Determination of core body temperature is essential to diagnose the presence and degree of hyperthermia, which is a frequent and rapidly fatal manifestation in patients with drug-induced delirium. Significant hyperthermia necessitates immediate interventions to achieve rapid cooling.^16,23,62 Some patients require temporary physical restraint to gain pharmacologic control and prevent personal harm to themselves or others. Physical restraints should be discontinued as soon as possible; prolonged restraints may result in rhabdomyolysis and continued heat generation. Intravenous access should be obtained so that intravenous sedation can be initiated. In the event that intravenous access cannot be obtained, it is necessary to attempt to administer intramuscular benzodiazepines such as midazolam until definitive access is made.

The most appropriate choice of chemical sedation is a benzodiazepine because of the characteristic high therapeutic index, good anticonvulsant activity, and predictable pharmacokinetic properties. The benzodiazepines are effective not only for the treatment of delirium induced by acute overdose of cocaine, amphetamines, and other xenobiotics but also the delirium associated with ethanol and sedative-hypnotic withdrawal (Antidotes in Depth: A23).^47,48,66,123 Sedation should be titrated rapidly until the patient is calm. In our clinical experience, cumulative benzodiazepine dosages required in the initial 30 minutes to achieve adequate sedation frequently exceed 100 mg of diazepam or its equivalent. Intravenous glucose (D₅₀W, 0.5–1 g/kg) and thiamine 100 mg should be given as indicated (Table 76–4).

Antipsychotics, particularly potent dopamine antagonists such as haloperidol and droperidol, are frequently recommended by others for amphetamine-induced delirium. Antipsychotics may antagonize some of the effects of amphetamines via dopamine blockade, but they have not been shown to be as effective as benzodiazepines in experimental models.^44,66,123 Additionally, antipsychotics may lower the seizure threshold, alter temperature regulation, cause acute dystonia, and precipitate cardiac dysrhythmias, and they do not interact with the benzodiazepine-GABA-chloride channel receptor complex. All of these effects may aggravate the clinical outcomes related to occult or concomitant cocaine toxicity and ethanol withdrawal.^66,69,123 Based on these concerns, benzodiazepines should be utilized as first-line treatments in the management of acute toxicity from amphetamines.

Rhabdomyolysis from amphetamines usually results from psychomotor agitation and hyperthermia.¹⁴³ Sedation prevents further muscle contraction and heat production. External cooling should be instituted for hyperthermia. Adequate intravenous hydration and cardiovascular support should maintain urine output of at least 1 to 2 mL/kg/h. Although urinary acidification can significantly increase amphetamine elimination and decrease the half-lives of amphetamine and methamphetamine,^11,12 pH manipulation does not decrease toxicity, and, in fact, it may increase the risk of acute kidney injury from rhabdomyolysis by precipitating ferrihemate in the renal tubules.⁴⁰ Patients with acute kidney injury, acidemia, and hyperkalemia may require urgent hemodialysis.

Amphetamine body packers, although uncommon, should be treated similarly to those who transport cocaine (Special Considerations: SC5). Any sympathomimetic symptom suggesting leakage of the packets requires surgical intervention.¹⁶⁸ Intravenous fluids, benzodiazepines, intubation, and external cooling may be necessary to stabilize these patients.

Methamphetamine

Methamphetamine is known by many names, including, but not limited to, “yaba,” “speed,” “go,” “crack,” “uppers,” and “dexies.” The terms “crystal,” “shard,” and “ice” refer to the crystalline form of methamphetamine. Methamphetamine was first synthesized from ephedrine in Japan in 1893, soon after the synthesis of amphetamine in 1887. Crystallized methamphetamine was synthesized in 1919 through the reduction of ephedrine using red phosphorus. From the 1950s to the 1970s, there were multiple epidemics of methamphetamine abuse in the United States.⁶⁴ Methamphetamine is approved by the FDA for the short-term treatment of attention-deficit/hyperactivity disorder and obesity, and it is sold under the trade name Desoxyn as a Schedule II drug. It is also prescribed for off-label use for refractory depression and narcolepsy.

The production of methamphetamine is relatively simple, requiring minimal equipment and chemicals. There are many methods of methamphetamine production which initially utilize pseudoephedrine, ephedrine, or phenyl-2-propone (P2P). The primary ingredient of methamphetamine synthesis is ephedrine, which can be hydrogenated into methamphetamine. The ephedrine method, using pharmaceutical grade l-ephedrine, produces a product with few contaminants that is stereochemically pure.^49,133 P2P, as an alternative ingredient, can be methylated into ephedrine and then transformed into methamphetamine.²² Because of the strict control of ephedrine and P2P, illicit chemists use phenylacetic acid to synthesize P2P.^22,42 Lead acetate, which is used as a substrate for the reaction, has resulted in an epidemic of lead poisoning associated with methamphetamine abuse in Oregon.^2,121 Mercury contamination was also documented, although clinical mercury toxicity has not been reported.²⁰ Methamphetamine laboratories use many xenobiotics, including phosphine gas, methylamine gas, chloroform, and hydrochloric acid^3,81; therefore, these laboratories pose a significant health risk to law enforcement officers and the general public, causing respiratory and ophthalmic irritation, headaches, and burns.^28,155 Currently, the sale of other potential amphetamine synthetic ingredients, such as hydrochloric acid, hydrogen chloride gas, anhydrous ammonia, red phosphorus, and iodine, are also monitored and restricted in the United States.^22,29

Methamphetamine exists as a chiral molecule with two isomers that include levomethamphetamine and dextromethamphetamine. Although the levorotatory form is devoid of CNS stimulatory properties, it retains its vasoactive effects and is used in nonprescription nasal decongestant inhalers. In the racemic mixture, the dextrorotatory form is responsible for the entire stimulant effects observed with methamphetamines. Methamphetamine undergoes metabolism in the liver mainly to amphetamine and 4-hydroxymethamphetamine and has prolonged half-life of 19 to 34 hours, although the duration of its acute effects can be greater than 24 hours.⁴⁹

3,4-Methylenedioxymethamphetamine (MDMA)

3,4-Methylenedioxymethamphetamine, also known as MDMA, was first synthesized in 1912, and was rediscovered in 1965 by Shulgin. MDMA is known as “ecstasy,” “E,” “Adam,” “XTC,” “molly,” and “MDM,” and it is commonly abused by college students and teenagers.^128,170,174 Other amphetamines that are similar to MDMA, include MDEA (“Eve”) and MDA (“love drug”), which have similar clinical effects, are also used or distributed as MDMA in areas of MDMA use. Amphetamines sold as MDMA include 2CB, 2,4-dimethoxy-4-(n)-propylthiophenylethylamine (2C-T7), and N-methyl-1-(3, 4-methylenedioxyphenyl)-2-butanamine (MBDB).^27,63,92 The term “ecstasy” may be used for all these xenobiotics. Typically, MDMA is available in 50 to 200 mg colorful and branded tablets.

MDMA and similar analogs are so-called entactogens (meaning touching within), capable of producing euphoria, inner peace, and a desire to socialize.¹⁵² In addition, some psychologists used MDMA to enhance psychotherapy until the Controlled Substances Act of 1986 placed MDMA in Schedule I, thereby eliminating its medical use.¹¹⁹ People who use MDMA report that it enhances pleasure, heightens sexuality, and expands consciousness without the loss of control.⁷⁰ Negative effects reported with acute use included ataxia, restlessness, confusion, poor concentration, and impaired memory.¹⁵² MDMA has about one-tenth the CNS stimulant effect of amphetamine. Unlike amphetamine and methamphetamine, MDMA is a potent stimulus for the release of serotonin.^24,45,72 The concentration of MDMA required to stimulate the release of serotonin is 10 times less than that required for the release of dopamine or norepinephrine. In animal models, the stereotypic and discriminatory effects of MDMA and its congeners can be distinguished from those of other amphetamines.²⁴

The sympathetic effects of MDMA are mild in low doses. However, when a large amount of MDMA is taken, the clinical presentation is similar to that of other amphetamines, and deaths can result from abuse.^61,91,138 Those patients at greatest risk develop dysrhythmias, hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation.¹³⁸ Significant hyponatremia is reported with MDMA use.^1,21,75 MDMA and its metabolites increase the release of vasopressin (antidiuretic hormone), and this may be related to the serotonergic effects.⁵⁶ Furthermore, substantial free water intake combined with sodium loss from physical exertion in dance clubs may exacerbate the development of hyponatremia.

Most recently, reports of poisoning from a form of MDMA known as Molly have emerged. Molly is initially thought to be a purified or crystallized form of MDMA that is typically taken orally. Molly use has increased due to what was perceived as a more rapid onset of symptoms and a subtler offset or “come down” period. Molly is also commonly viewed as a safer form of MDMA, since it is believed to contain no adulterants. The use of Molly is associated with adverse effects such as intracranial hemorrhage.⁸⁵ While Molly is often sold on the street as MDMA, Molly may not be pure MDMA but actually may contain 2C compounds, amphetamines that have two methoxy groups and a halogen such as iodine (2C-I) or bromide (2C-B). The compound 2C-I is known as “smiles.”

A major concern with MDMA use is its long-term effects on the brain. In numerous animal models, acute administration of MDMA leads to the decrease in serotonin reuptake transporter (SERT) function and number. Recovery of SERT function may take several weeks. Repetitive administration of MDMA ultimately results in permanent damage to serotonergic neurons, typically causing injury to the axons and the terminals while sparing the cell bodies.^112,140,141 Some regeneration of synaptic terminals can occur even with neuronal damage, but functional recovery is incomplete. Intact SERT function is necessary for MDMA-induced neurotoxicity. Xenobiotics that inhibit the reuptake of serotonin prevent MDMA-induced neurotoxicity in animals. Animal data suggest that MDMA induces hydroxyl free-radical generation and decreases antioxidants in serotonergic neurons.¹⁴⁹ MDMA itself is not the ultimate neurotoxin, rather its metabolites 3-methyldopamine and N-methyl-α-methyldopamine appear to be responsible in animals.¹¹⁶ When antioxidants are depleted, neuronal damage may occur.

Paramethoxyamphetamine (PMA) and Paramethoxymethamphetamine (PMMA)-Monomethoxy Derivatives

Para-methoxyamphetamine (PMA) is the 4-methoxylated analog of amphet-amine, and para-methoxy-N-methylamphetamine (PMMA; methyl-MA) is the 4-methoxy analog of methamphetamine. PMA was first produced in 1973 and sold as a hallucinogen for a short period of time, and it reemerged in the 1990s. PMMA soon appeared after PMA, with multiple reports of death also emerging during that time.^10,83,97,102 PMA and PMMA are commonly found as tablets or capsules sold as MDMA or “ecstasy.” While the effects of PMA and PMMA mimic some aspect of MDMA and methamphetamine, there are unique properties of PMA and PMMA, that make them considerably more lethal and earning the street name “death.” In recent years, there have been more than 100 fatalities and severe poisonings attributed to PMMA and PMA in the United States, Canada, and Europe.^{87,100,103,107,109}

Methoxy ring substitution of amphetamine or methamphetamine at the 3 or 4 positions (para substitution is the most common) yields PMA and PMMA derivatives that have significantly less sympathomimetic activity than amphetamine but very potent serotonergic activity.^38,158 Both PMA and PMMA inhibit reuptake of serotonin and inhibit monoamine oxidase A found centrally and peripherally. The methoxy ring substitution is also responsible for poor penetration of the blood brain barrier.^6,58

PMA and PMMA poisoning lead to autonomic hyperactivity similar to what is observed in other amphetamines such as hypertension, tachycardia, and agitation. The use of PMA and PMMA results in a weak euphoric effect and delayed onset of CNS effects due to poor blood–brain barrier penetration. These properties will often lead users to repeatedly dose themselves that result in serious toxicity and are responsible for the seemingly high mortality rate.

Cathinones (Methcathinone, MDPV, and Mephedrone)—”Bath Salts”

Cathinone ({S}-2-amino-1-phenyl-1-propanone) is a naturally occurring substance found in the leaves of the Catha edulis (khat) plant. Also known as guat and gat, the fresh leaves and stems are commonly used as a stimulant in Africa and certain Middle Eastern countries such as Yemen. While there are numerous other amphetamines in minute quantities, the primary active ingredient is cathinone. As the leaves age, cathinone is degraded to cathine, which has about one-tenth the stimulant effect of d-amphetamine. Imported fresh khat must be consumed within a week, before it loses much of its potency. The primary effects of khat are increased alertness, insomnia, euphoria, anxiety, and hyperactivity. Khat chewing is linked to cardiac and gastrointestinal disease.^125,126

The syntheses of cathinone derivatives were reported in the early 1920s, with the production of methcathinone in 1928 and mephedrone in 1929. Methcathinone, the methyl derivative of cathinone, was used in Russia as an antidepressant in the 1930s and 1940s. Also known as “Cat” and “Jeff,” cathinone has been used recreationally, most often in countries formerly part of the Soviet Union, but it also gained popularity in the United States, particularly in Michigan, in the 1990s. Synthetic cathinones have become popular drugs of abuse due to a combination of media attention and widespread Internet availability.^134,150 Many other synthetic cathinones have been produced including methylone, mephedrone, butylone, methylenedioxypyrovalerone (MDPV), dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, and MDPV.

The synthetic cathinones differ from other amphetamines because they contain a ketone at the β position. For this reason, they are often known as bk-amphetamines. The β-ketone group is responsible for increased polarity, which decreases penetration of the blood–brain barrier. They possess amphetaminelike properties and have sympathomimetic effects, although as a group, they are considered less potent. Some of the synthetics cathinones are reported to cause hyponatremia. Although the mechanism is not clear and may not be similar to MDMA.^{9,25,26,108,130} Reported complications include compartment syndrome, acute kidney injury, and sudden cardiac death.^{101,118,139,144,179} An irreversible Parkinson syndrome was also described in chronic users of intravenous methcathinone, particularly in Europe and Russia. The methcathinone was manufactured with the use of potassium permanganate to oxidize ephedrine or pseudoephedrine. In one case series, T1-weighted magnetic resonance imaging showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all active methcathinone users, suggestive of manganese poisoning, which was also confirmed with elevated whole blood concentrations.¹⁵⁹

Synthetic cathinones are often sold as “bath salts” or “plant food” and labeled as “not for human consumption” in an attempt to circumvent controlled substances legislation. The legal status differs among countries and changes over time. In the United States, the synthetic cathinones were initially unscheduled, but they are illegal for human consumption under the Federal Analogue Act of 1986. However, on September 7, 2011, the Drug Enforcement Administration used its emergency scheduling authority to enact temporary control, making possession or sale of methylenedioxypyrovalerone, methylone, and mephedrone illegal until recently, when permanent law has been enacted.

Bromo-dragonFLY

1-(8-Bromobenzo[1,2-b;4,5-b′]difuran-4-yl)-2-aminopropane, also known as Bromo-dragonFLY (BDF), was first synthesized in 1998. BDF was named after its superficial structural resemblance to a dragonfly, similar to earlier and the less potent dihydrofuran series of compounds nicknamed FLY. BDF is a member of a new class of benzodifurans, which have been used as a potent research tools for investigation of the serotonin receptor family and for a time as potential antidepressants.

Structurally, BDF is closely related to other phenylethylamines suchas DOB and 2C-B. BDF contains two furan rings on either side of the benzene ring, creating a fully aromatic tricyclic structure. There are a number of similar compounds to BDF, differing by substitution of the bromide atom with other entities. BDF exists as R- and S-enantiomers, which are both biologically active. The R-enantiomer is considered more potent, with its potent hallucinogenic effect mediated through the 5-HT_2A serotonin receptor (also with affinity for the 5-HT_2B and 5-HT_2C serotonin receptors).¹²⁷

BDF is associated with deaths in Europe and the United States. Reports demonstrate delayed complications from severe peripheral vasoconstriction and limb ischemia that likely result from the potent serotonergic properties of BDF.^4,37,166,175

2,5-Dimethoxy-4-Methylamphetamine (DOM) and 2,5-Dimethoxy-4-Iodoamphetamine (DOI)

2,5-Dimethoxy-4-methylamphetamine (DOM), also known as STP, which stands for “Serenity, Tranquility, and Peace,” emerged in the 1960s as a hallucinogen. It was noted for its delayed onset of action and duration of effect that quickly led to its short-lived appearance. 2,5-Dimethoxy-4-iodoamphetamine (DOI) is another potent hallucinogen, previously sold as a substitute for lysergic acid diethylamide, or LSD.

Dimethoxy amphetamine derivatives are structurally characterized by methoxy ring substitution at the 2 and 5 positions on the aromatic ring, with varying additional substitution of hydrophobic moieties at the 4 position. DOM and DOI are both serotonin receptor agonists with selectivity at the 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor subtypes. Due to this selectivity, DOM and DOI are often used in scientific research involving study of the 5-HT₂ receptor subfamily. DOM exists as a chiral molecule, with the R-(-)-enantiomer considered the more potent.¹³

Potent hallucinogenic effects and dysphoria characterize the use of DOB and DOI, with minimal sympathomimetic effects. These symptoms can often be delayed with a prolonged duration of effect, sometimes refractory to the use of benzodiazepines. There is also report of reversible vasospasm with the use of these dimethoxy amphetamine derivatives.^8,19

• Amphetamines, often created to evade designer drug laws, continue to increase dramatically throughout the United States.

• The extensive knowledge with regard to the modifications to the existing phenylethylamine backbone allows clinicians to predict the effects of the amphetamines. These effects are attributed to variable degrees of selectivity affecting dopamine, norepinephrine and serotonin.

• Many complications associated with amphetamines are similar to those of cocaine, such as agitation, hyperthermia, rhabdomyolysis, myocardial ischemia, and cerebral infarction.

• The management of acute amphetamine toxicity includes supportive care, with the judicious use of benzodiazepines and anticipation of complications of adrenergic toxicity such as hyperthermia and rhabdomyolysis.

Acknowledgment

William K. Chiang, MD, contributed to this chapter in previous editions.

References