The term “amphetamine” includes a wide range of amine compounds with sympathetic-like effects. The simplest member of this group is amphetamine, but there are hundreds of molecules with related chemical structures that have similar clinical effects. This chapter will focus on the more important and commonly used licit and illicit members of this group.

Amphetamine and methamphetamine are the most well-known members of this class. Amphetamine or alpha- methyl phenylethylamine was first synthesized over 120 years ago, and it was widely used by many (including the U.S. military) as the stimulant Benzedrine, beginning in the 1930s. Restricting to
prescription decreased use slightly, but it has been continued to be used for both licit (Attention deficit hyperactivity disorder [ADHD], narcolepsy, and weight loss) and illicit reasons. Currently, Adderall® (a mixture of l and d amphetamine) and Vyvanse® (Lisdexamfetamine; metabolized to d-amphetamine) are two commonly used medicinal amphetamine preparations.

Methamphetamine (or N-methyl amphetamine) is undergoing a surge in United States and worldwide popularity. One reason for its popularity over amphetamine is its longer duration of action. Another reason is that the Drug Enforcement Agency has taken actions to limit the availability of precursor compounds for the synthesis of amphetamine, including the unrelated removal of phenylpropanolamine from the OTC market. Finally, synthesis can be conducted by individuals without specialized training using materials that are not difficult to obtain, resulting in a relatively pure product. Currently, Desoxyn® is a methamphetamine containing prescription preparation used for ADHD and obesity.

There are several other medicinal compounds that have clinical effects similar to amphetamines, with a select few discussed here. Ritalin® (methylphenidate) is commonly used in children for ADHD and is occasionally abused. Phenylpropanolamine (Dexatrim®) was used more extensively in the past as a decongestant and weight loss agent; in 2005 the FDA removed it from OTC sales due to concerns about increased stroke risk and it is no longer available as an Rx [1]. Ephedrine has been used extensively in the past in herbal weight loss/energy preparations as well as a decongestant in cough/cold preparations; but in 2004, the FDA prohibited the sale of dietary supplements containing ephedra (ephedrine and pseudoephedrine) over safety concerns. Additionally, in 2006, requirements regulating the sale of ephedrine were enacted in an attempt to limit its diversion for methamphetamine synthesis. Phentermine is an amphetamine derivative that is used for appetite suppression. Selegiline is an amphetamine derivative with selective monoamine oxidase inhibitor (MAOI)-B effects that is metabolized to l-methamphetamine. Propylhexedrine (Benzedrex® nasal inhaler), although not a true amphetamine, has sympathomimetic and vasoconstrictor properties and is occasionally abused.

Some amphetamine analogs with aromatic ring substitutions have direct affinity for serotonin receptors as well as increased inhibition of serotonin uptake, thereby exerting both sympathomimetic and serotonergic effects manifested by hallucinatory properties. One of the more popular compounds in this group is 3,4-methylenedioxy-methamphetamine (MDMA or Ecstasy). Other similar ring-substituted amphetamine compounds include 3,4-methylenedioxy amphetamine (MDA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA or Eve), 2,5-dimethoxy-4-bromo-phenethylamine (2-CB; not strictly an amphetamine), para-methoxy amphetamine (PMA), 2,5-dimethoxy-4-methyl-amphetamine (DOM), and 2,5 dimethoxy-4-bromo-amphetamine (DOB; also the similar chlorine and iodine derivatives DOC and DOI exist). The 2,5 dimethoxy halogenated amphetamine derivatives (DOB, DOC, DOI) are common substitutions for LSD found on blotter paper in the United States [2].

Recent increases in clandestine methamphetamine production facilities (“meth labs”) have resulted in concern for environmental contamination and bystander toxicity from laboratory chemicals. The vast majority of illicit amphetamine laboratories currently produce methamphetamine by reductive dehydroxylation of ephedrine or pseudoephedrine. Methamphetamine laboratories are often discovered after a chemical mishap or explosion and are a health risk due to the chemicals used, which include respiratory irritants and caustics [3]. Methcathinone is a potent, occasionally used amphetamine-like substance produced from the oxidation of ephedrine in amateur labs, instead of the usual reduction to methamphetamine; toxicity is similar except that cases of Parkinson-like neurotoxicity from manganese in the impure product have been reported.

There are two methods most commonly being utilized for methamphetamine synthesis. The one resulting in the cleanest product probably the more dangerous one is the Birch or “Nazi” method, which utilizes lithium metal as the reducing agent dissolved in anhydrous ammonia. The other method is the hydriodic acid method, which usually utilizes red phosphorus and iodine, as the availability of hydriodic acid is restricted.

Depending upon the illicit amphetamine purchased, there is a chance that it will contain one or more contaminants, or possibly be substituted by another sympathomimetic. Street purchased methamphetamine tends to be of better purity than cocaine, while MDMA is very commonly substituted or combined with other psychoactive substances. The exact “contaminants” or other chemicals present in street purchased amphetamines are highly variable based on drug, year, and location. Previously reported substitutions include acetaminophen, anesthetics (benzocaine, lidocaine, procaine), cocaine, caffeine, ephedrine, ketamine, lead (rare), talc, phencyclidine, piperazine compounds (benzylpiperazine and others), phenylpropanolamine, pseudoephedrine, strychnine, and quinine [4]. Depending on the quantity of the adulterant, it may contribute to the effect or toxicity of the sympathomimetic drugs.

Occasionally, an individual will ingest an amphetamine while it is wrapped in plastic or other non-permeable material. Body packers or “mules,” are people who transport large quantities of specially prepared drug packets in their gastrointestinal (GI) tract. Each packet usually contains drugs in sufficient quantity and purity to cause life-threatening toxicity if rupture occurs. Body stuffers are people who quickly swallow (“stuff”) drug-containing packets in an attempt to get rid of evidence and avoid arrest by the police. These packets are usually poorly prepared and are at increased risk of leakage and rupture, but often contain far less drug than a packet from a body packer. Rarely, individuals will ingest a plastic bag containing a drug with holes or a corner of the bag cut off in an attempt to produce a sustained release effect [5].

Amphetamine and methamphetamine are similar in their pharmacokinetic properties and have similar physiological effects in humans [6]. They do not have significant direct effects at adrenergic or dopamine receptors; rather their effects are mediated by an increase in the concentration of synaptic dopamine and to a lesser extent, serotonin and norepinephrine. This increase occurs by several mechanisms. Amphetamine and methamphetamine enter the presynaptic cytoplasm by passive diffusion and uptake by biogenic amine uptake transporters. Amphetamine moves into the synaptic vesicles by diffusion and by the vesicular monoamine transporters (VMATs), subsequently causing release of stored dopamine and norepinephrine, most likely by collapsing the proton gradient as well as an effect on VMAT. This increases the cytosolic levels of these biogenic amines, which then results in increased synaptic levels due to increased reverse transport activity by the amine transporters, especially the dopamine transporter. Part of the mechanism of action of amphetamines’ raising synaptic levels is also due to competitive inhibition of biogenic amines reuptake from the synapse into the presynaptic terminal. Finally, some amphetamines have MAOI activity, which inhibits the breakdown of dopamine, serotonin, and norepinephrine, with some (PMA for example) having significant MAOI activity [7,8].

The mechanism of action of MDMA toxicity includes a direct effect at some serotonin receptors, as well as some of the
indirect effects described above mediated by a release of serotonin. Additionally, human and animal studies have shown that MDMA produces a dose-related depletion of serotonin and serotonin transporter activity, and produces serotonergic neuronal degeneration [9]. Methamphetamine causes dopamine and serotonergic neuronal toxicity as well as a decrease in dopamine, VMAT, and serotonin transporter activity in the brain, at least in part by free radical injury [10,11].

Peak plasma concentrations of methamphetamine are reported within 4 hours for an insufflated dose, within 2 to 3 hours for a smoked dose and nearly immediate for an IV dose [12,13]; however levels do not correlate with the degree of clinical toxicity [14]. Methamphetamine and amphetamine have an l and d isomer; the d form is more potent in causing pleasurable CNS stimulation and persistent cardiovascular activation than the l form [15]. Most abused methamphetamine is the d isomer, having been synthesized from ephedrine or pseudoephedrine. However, the d form of methamphetamine has a shorter half-life (10 to 11 hours) than the l form (13 to 15 hours) [15,13]. The α-carbon on the amphetamine molecule protects it against MAO degradation. The majority of methamphetamine is either eliminated unchanged, N-demethylated to amphetamine (active) or hydroxylated to p-hydroxymethamphetamine (active) with contribution from cytochrome 2D6 [16,17]; amphetamine undergoes a similar metabolism, except that it is deaminated to an inactive metabolite as well as hydroxylated to p-hydroxyamphetamine (active). Excretion of both is increased in acidic urine, but this fact has no clinical utility as the risks of urinary acidification outweigh any potential benefits. Urine usually remains positive for 24 hours or longer in high dose chronic abusers [18]. The serotonergic amphetamine and amphetamine-like compounds (MDMA, PMA, 2-CB) are not metabolized to amphetamine or methamphetamine.

Methamphetamine toxicity has been reported following ingestion, inhalation (smoking), insufflation (intranasal), rectal, subcutaneous, intramuscular, and intravenous exposure [19]. The onset and duration of methamphetamine toxicity depends on factors such as dose, route of exposure, individual tolerance, pattern of use, ambient temperature, and crowding/stimulation level. Most people develop signs and symptoms within a few minutes of parenteral drug use, whereas signs and symptoms may be delayed for hours after ingestion with body packers and body stuffers. In most patients, the majority of sympathomimetic effects are expected to resolve within 24 to 36 hours post exposure [19]. Life-threatening toxicity is more common in drug abusers and in people who overdose with suicide intent, and it can also occur in body packers and body stuffers.

Methamphetamine toxicity usually results in a group of signs and symptoms known as the “sympathomimetic toxidrome,” including hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, mydriasis, hyperactive bowel sounds, agitation, anxiety, and toxic psychosis. This pattern of symptoms is seen for other members of the amphetamine group as well as other sympathomimetics like cocaine and caffeine; but this pattern of symptoms can be variable depending on the sympathomimetic agent involved. For example, phenylpropanolamine has peripheral alpha vasoconstrictive effects that can result in a reflex bradycardia.

Airway and breathing abnormalities are uncommon with ingestion. Transient cough, pleuritic chest pain, and shortness of breath are common after insufflation or smoking. People present in illicit drug laboratory fires and explosions may have thermal injury to their oropharyngeal or upper airway. Insufflation or smoking methamphetamine may result in bronchospasm, pneumothorax, pneumomediastinum, pneumonitis, and noncardiogenic pulmonary edema. Noncardiogenic pulmonary edema and acute respiratory distress syndrome may be associated with multisystem organ failure. Tachypnea is common secondary to agitation or metabolic acidosis. Hypoventilation is rare but may occur secondary to intracranial pathology or the end stage of multisystem organ failure.

Many of the adverse cardiovascular effects result from increases in peripheral catecholamines, which result in a mismatch of oxygen consumption and delivery; there may be a direct cardiotoxic effect of methamphetamine as well. Palpitations and chest pain are common complaints. Acute myocardial infarction due to vasospasm, plaque rupture, and/or thrombosis can occur [20]. Life-threatening atrial or ventricular dysrhythmias, sudden death, and aortic dissection have been reported, with potential synergy if cocaine is also present [21,20]. Coronary artery disease and cardiomyopathy have been reported with chronic amphetamine abuse [14,22,23]. Peripheral vascular ischemia can result from oral sympathomimetic abuse but is uncommon unless an inadvertent intra-arterial injection occurs. Hypotension is unusual but may be secondary to dehydration, myocardial depression, intestinal ischemia, or sepsis.

There are several important findings that may be apparent on the Head-Eyes-Ears-Nose-Throat exam. Mydriasis is common and various forms of nystagmus have been reported. Patients who abuse and binge on sympathomimetic agents are often dehydrated and have dry mucous membranes. Nasal mucosal abnormalities, including nasal septal perforations, are well reported in patients who chronically insufflate cocaine and are possible with insufflation of other sympathomimetics. An increase in dental pathology has been noted in users of methamphetamines, manifested by a distinctive pattern of caries on the buccal smooth surfaces of the posterior teeth and the interproximal surfaces of the anterior teeth. The teeth may be loose, rotting, or crumbling, and are usually beyond salvage. The pathology of these changes is uncertain, but is believed to be due to a combination of decrease in salivation (xerostomia) along with increased ingestion of sugar- and acid-containing sodas, poor hygiene, poor nutrition, localized vasospasm, and bruxism, a side effect especially seen with MDMA. [24,25,26].

Central nervous system effects are the reason for abuse as well as often the reason for seeking care. Methamphetamine produces a euphoric and anorexic effect, with smoked and injected administration producing a greater “rush.” The most common presenting symptoms include agitation and altered mental status; other symptoms include headache, hyperactivity, agitation, toxic psychosis, loss of consciousness, focal neurologic deficits, and seizures [27,19]. Hyperthermia may be more common and worse in patients with uncontrolled psychomotor agitation, especially when patients are physically but not chemically restrained. Altered mental status may be secondary to hypoglycemia or an acute intracranial process. Headache may be secondary to intracranial or subarachnoid hemorrhage [21,14,28,29]. Focal neurological deficit may be secondary to cerebral ischemia or infarction, vasospasm, or direct injection trauma. On arteriography, multiple occlusions or “beading” has been observed of the arteries; this is thought to represent some combination of local vasospasm or vasculitis [30,1,28]. Seizures may occur in association with and independent of intracranial hemorrhage or cerebral infarction. Prolonged methamphetamine (and probably MDMA) use may lead to cognitive decline represented by attention and memory changes [11].