Dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) are used for the treatment of narcolepsy and for attention-deficit disorders in children. Methamphetamine (“crank,” “speed”), 3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”), paramethoxyamphetamine (PMA), and several other amphetamine derivatives, as well as a number of prescription drugs, are used as illicit stimulants and hallucinogens (see also “Lysergic Acid Diethylamide [LSD] and Other Hallucinogens”). “Ice” is a high purity, smokable crystalline form of methamphetamine. Methamphetamine precursors such as pseudoephedrine, ephedrine, and other over-the-counter decongestants are discussed. Several amphetamine-related drugs (benzphetamine, diethylpropion, phendimetrazine, phenmetrazine, and phentermine) are marketed as prescription anorectic medications for use in weight reduction (Table II-1). Fenfluramine and dexfenfluramine were marketed as anorectic medications but were withdrawn from the market in 1997 because of concerns about cardiopulmonary toxicity with long-term use.

Cathinone (found in the shrub Catha edulis, or khat), methcathinone, and mephedrone (4-methylmethcathinone) are chemically related drugs with amphetamine-like effects. Newer synthetic analogs, such as 3,4-methylenedioxypyrovalerone and various derivatives of methcathinone, are becoming popular drugs of abuse, often sold on the Internet as “bath salts” with names such as “Ivory Wave,” “Bounce,” “Bubbles,” “Mad Cow,” and “Meow Meow.” Piperazine-like compounds such as 1-benzyl-piperazine (BZP), 1-(4-methoxyphenyl)-piperazine (pMeOPP), 1-(3-chlorophenyl)-piperazine (mCPP), and 1-(3-trifluoromethylphenyl)-piperazine (TFMPP) are also designer drugs of abuse with stimulant effects.

Atomoxetine is a specific norepinephrine reuptake inhibitor approved as a nonstimulant alternative for the treatment of attention-deficit/hyperactivity disorder (ADHD). Modafinil is a nonamphetamine stimulant used in the treatment of narcolepsy, sleep disorders associated with shift work, and sleep apnea.

1. Amphetamine and related drugs activate the sympathetic nervous system via CNS stimulation, peripheral release of catecholamines, inhibition of neuronal reuptake of catecholamines, and inhibition of monoamine oxidase. Amphetamines, particularly MDMA, PMA, fenfluramine, and dexfenfluramine, also cause serotonin release and block neuronal serotonin uptake. The various drugs in this group have different profiles of catecholamine and serotonin action, resulting in different levels of CNS and peripheral stimulation.
2. Modafinil is a nonamphetamine stimulant. Its mechanism of action is unclear, but extracellular CNS levels of dopamine, norepinephrine, serotonin, histamine, and glutamate are increased while gamma aminobutyric acid (GABA) is decreased. Atomoxetine is a specific norepinephrine reuptake inhibitor.
3. Piperazine-like compounds have stimulant properties and enhance the release of catecholamines particularly dopamine and serotonin.
4. Pharmacokinetics. All these drugs are well absorbed orally and have large volumes of distribution (Vd = 3-33 L/kg), except for pemoline (Vd = 0.2-0.6 L/kg), and they are generally extensively metabolized by the liver. Excretion of most amphetamines is highly dependent on urine pH, with amphetamines eliminated more rapidly in an acidic urine (see also Table II-63). There is limited pharmacokinetic data for piperazine-like compounds.

These drugs generally have a low therapeutic index, with toxicity at levels only slightly above usual doses. However, a high degree of tolerance can develop after repeated use. Acute ingestion of more than 1 mg/kg of dextroamphetamine (or an equivalent dose of other drugs; see Table II-1) should be considered potentially life-threatening.

1. Acute CNS effects of intoxication of amphetamines include euphoria, talkativeness, anorexia, anxiety, restlessness, agitation, psychosis, seizures, and coma. Intracranial hemorrhage may occur owing to hypertension or cerebral vasculitis.
2. Acute peripheral manifestations include sweating, tremor, muscle fasciculations and rigidity, bruxism, tachycardia, hypertension, acute myocardial ischemia, and infarction (even with normal coronary arteries). Inadvertent intra-arterial injection may cause vasospasm resulting in gangrene; this has also occurred with oral use of DOB (2,5-dimethoxy-4-bromoamphetamine; see “Lysergic Acid Diethylamide [LSD] and Other Hallucinogens”).
3. Death may be caused by ventricular arrhythmia, status epilepticus, intracranial hemorrhage, or hyperthermia. Hyperthermia frequently results from seizures and muscular hyperactivity and may cause brain damage, rhabdomyolysis, and myoglobinuric renal failure.
4. Acute modafinil and atomoxetine overdoses are generally mild to moderate in severity. Overdoses of modafinil up to 8 g are generally well tolerated with neurological complaints of anxiety, agitation, headaches, dizziness, insomnia, tremors, and dystonia. Similarly, overdoses of atomoxetine are usually mild and present with drowsiness, agitation, hyperactivity, GI upset, tremor, hyperreflexia, tachycardia, hypertension, and seizures.
5. Acute exposures to piperazine-like compounds including BZP, pMeOPP, mCPP, and TFMPP result in palpitations, agitation, anxiety, confusion, dizziness, insomnia, headache, hallucinations, depression, paranoia, tremor, mydriasis, urinary retention, nausea, and vomiting. Seizures have also been reported along with multi-organ failure. Symptoms have persisted for up to 24 hours after ingestion. Consistent with sympathomimetic effects, patients often present with tachycardia and hypertension.
6. Chronic effects of amphetamine abuse include weight loss, cardiomyopathy, pulmonary hypertension, dental changes, stereotypic behavior (eg, picking at the skin), paranoia, and paranoid psychosis. Psychiatric disturbances may persist for days or weeks. After cessation of habitual use, patients may experience fatigue, hypersomnia, hyperphagia, and depression lasting several days.
7. Prolonged use (usually 3 months or longer) of fenfluramine or dexfenfluramine in combination with phentermine (“fen-phen”) has been associated with an increased risk for pulmonary hypertension and fibrotic valvular heart disease (primarily aortic, mitral, and tricuspid regurgitation). The pathology of the valvular disease is identical to that seen with carcinoid syndrome.
8. Illicit manufacture of methamphetamine can expose the “chemist” and his or her family to various toxic chemicals, including corrosive agents, solvents, and heavy metals.

Is usually based on a history of amphetamine use and clinical features of sympathomimetic drug intoxication.

1. Specific levels. Amphetamines and many related drugs can be detected in blood, urine and gastric samples, providing confirmation of exposure. However, quantitative serum levels do not closely correlate with the severity of clinical effects and are not generally available. Amphetamine derivatives and adrenergic amines may cross-react in immunoassays (see Table I-32), and distinguishing the specific drug requires confirmatory testing (eg, with thin-layer chromatography, gas chromatography [GC], or GC/mass spectrometry). Selegiline (a drug used in Parkinson disease) is metabolized to l-amphetamine and l-methamphetamine, and Clobenzorex (an anorectic drug sold in Mexico) is metabolized to amphetamine; these drugs can produce a positive result for amphetamines on urine and blood tested with immunoassays (unless a specific monoclonal antibody amphetamine assay is used) or GC/mass spectrometry (unless a special chiral derivative or column is used). Amphetamine, methamphetamine, and MDMA can be screened for by using hair and liquid chromatography-mass spectrometry.
2. Other useful laboratory studies include electrolytes, glucose, BUN and creatinine, creatine kinase (CK), urinalysis, urine dipstick test for occult hemoglobin (positive in patients with rhabdomyolysis with myoglobinuria), 5-HIAA (for suspected carcinoid syndrome), cardiac troponin, ECG and ECG monitoring, and CT scan of the head (if hemorrhage is suspected). Echocardiography and right heart catheterization may be useful for detecting valvular disease or pulmonary hypertension.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat agitation, seizures, coma, and hyperthermia if they occur.
   3. Continuously monitor the temperature, other vital signs, and the ECG for a minimum of 6 hours.
2. Specific drugs and antidotes. There is no specific antidote.
   1. Agitation.Benzodiazepines are usually satisfactory, although antipsychotic agents may be added as needed.
   2. Hypertension is best treated with sedation and, if this is not effective, a parenteral vasodilator such as phentolamine or nitroprusside.
   3. Treat tachyarrhythmias with propranolol or esmolol. Note: Paradoxical hypertension is postulated to occur due to unopposed alpha-adrenergic effects when beta₂-mediated vasodilation is blocked; be prepared to give a vasodilator (see Item B.2 above) if needed.
   4. Treat arterial vasospasm as described for ergots.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly. Consider whole-bowel irrigation and repeated doses of charcoal after ingestion of drug-filled packets (“body stuffers”).
4. Enhanced elimination. Dialysis and hemoperfusion are not effective. Repeat-dose charcoal has not been studied. Renal elimination of dextroamphetamine may be enhanced by acidification of the urine, but this is not recommended because of the risk for aggravating the nephrotoxicity of myoglobinuria.