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Amphetamines

by Patrick G. O’Connor, MD, MPH

Amphetamines are sympathomimetic drugs with CNS stimulant and euphoriant properties whose toxic adverse effects include delirium, hypertension, seizures, and hyperthermia (which can cause rhabdomyolysis and renal failure). Toxicity is managed with supportive care, including IV benzodiazepines (for agitation, hypertension, and seizures) and cooling techniques (for hyperthermia). There is no stereotypical withdrawal syndrome.

The original drug in this class, amphetamine, has been modified by various substitutions on its phenyl ring, resulting in many variations, including methamphetamine, methylenedioxymethamphetamine (MDMA or Ecstasy), methylenedioxyethylamphetamine (MDEA), and numerous others.

Some amphetamines, including dextroamphetamine, methamphetamine, and the related methylphenidate, are widely used medically to treat attention-deficit hyperactivity disorder, obesity, and narcolepsy, thus creating a supply subject to diversion for illicit use. Methamphetamine is easily manufactured illicitly.

Pathophysiology

Amphetamines enhance release of catecholamines, increasing intrasynaptic levels of norepinephrine, dopamine, and serotonin. The resulting marked α- and β-receptor stimulation and general CNS excitation account for the “desired” effects of increased alertness, euphoria, and anorexia, as well as the adverse effects of delirium, hypertension, hyperthermia, and seizures. Effects of amphetamines are similar, varying in intensity and duration of psychoactive effects; MDMA and its relatives have more mood-enhancing properties, perhaps related to a greater effect on serotonin. Amphetamines can be taken orally as pills or capsules, nasally by inhaling or smoking, or by injection.

Chronic effects

Repeated use of amphetamines induces dependence. Tolerance develops slowly, but amounts several 100-fold greater than the amount originally used may eventually be ingested or injected. Tolerance to various effects develops unequally. Tachycardia and increased alertness diminish, but hallucinations and delusions may occur.

Amphetamines typically cause erectile dysfunction in men but enhance sexual desire. Use is associated with unsafe sex practices, and users are at increased risk of sexually transmitted infections, including HIV infection. Amphetamine abusers are prone to injury because the drug produces excitation and grandiosity followed by excess fatigue and sleepiness.

Symptoms and Signs

Acute effects

Many psychologic effects of amphetamines are similar to those of cocaine; they include increased alertness and concentration, euphoria, and feelings of well-being and grandiosity. Palpitations, tremor, diaphoresis, and mydriasis may also occur during intoxication.

Binges (perhaps over several days) lead to an exhaustion syndrome, involving intense fatigue and need for sleep after the stimulation phase.

Toxicity or overdose

Tachycardia, arrhythmias, chest pain, hypertension, dizziness, nausea, vomiting, and diarrhea can occur. CNS effects include acute delirium and toxic psychosis. Overdose can also cause stroke (usually hemorrhagic), seizures, muscle rigidity, and hyperthermia (> 40° C); all of these effects may precipitate rhabdomyolysis, which can lead to renal failure.

Chronic effects

A paranoid psychosis may result from long-term use; rarely, the psychosis is precipitated by a single high dose or by repeated moderate doses. Typical features include delusions of persecution, ideas of reference (notions that everyday occurrences have special meaning or significance personally meant for or directed to the patient), and feelings of omnipotence. Some users experience a prolonged depression, during which suicide is possible. Recovery from even prolonged amphetamine psychosis is usual but is slow. The more florid symptoms fade within a few days or weeks, but some confusion, memory loss, and delusional ideas commonly persist for months.

Users have a high rate of severe tooth decay affecting multiple teeth; causes include decreased salivation, acidic combustion products, and poor oral hygiene.

Withdrawal

Although no stereotypical withdrawal syndrome occurs when amphetamines are stopped, EEG changes occur, considered by some experts to fulfill the physical criteria for dependence. Abruptly stopping use may uncover or exacerbate underlying depression or precipitate a serious depressive reaction. Withdrawal is often followed by 2 or 3 days of intense fatigue or sleepiness and depression.

Diagnosis

  • Clinical evaluation

  • Testing as needed to exclude serious nondrug-related disorders (eg, causing altered mental status)

Diagnosis is usually made clinically, although when history of drug use and the diagnosis are unclear, tests are done as indicated for the undifferentiated patient with altered mental status, hyperpyrexia, or seizures. Evaluation then typically includes CT, lumbar puncture, and laboratory tests to identify infections and metabolic abnormalities. Amphetamines are usually part of routine urine drug screens (see Drug Testing), which are done unless history of ingestion is clear; specific drug levels are not measured. Immunoassay urine screening tests for amphetamines may produce false-positive results and may not detect methamphetamine and methylphenidate.

Treatment

  • IV benzodiazepines

  • IV nitrates for hypertension unresponsive to benzodiazepines as needed

  • Cooling for hyperthermia as needed

Toxicity or overdose

When significant oral toxicity is recent (eg, < 1 to 2 h), activated charcoal may be given to limit absorption, although this intervention has not been shown to reduce morbidity or mortality. Urinary acidification hastens amphetamine excretion, but it may worsen myoglobin precipitation in the renal tubules and thus is not recommended.

Benzodiazepines are the preferred initial treatment for CNS excitation, seizures, tachycardia, and hypertension. Lorazepam 2 to 3 mg IV q 5 min titrated to effect may be used. High doses or a continuous infusion may be required. Propofol, with mechanical ventilation, may be required for severe agitation. Hypertension that does not respond to benzodiazepines is treated with nitrates (occasionally nitroprusside) or other antihypertensives as needed, depending on the severity of the hypertension. β-Blockers (eg, metoprolol 2 to 5 mg IV) may be used for severe ventricular arrhythmias or tachycardia.

Hyperthermia can be life threatening and should be managed aggressively with sedation plus evaporative cooling, ice packs, and maintenance of intravascular volume and urine flow with IV normal saline solution.

Phenothiazines lower seizure threshold, and their anticholinergic effects can interfere with cooling; thus, they are not preferred for sedation.

Withdrawal and rehabilitation

No specific treatment is needed. BP and mood should be monitored initially. Patients whose depression persists for more than a brief period after amphetamines are stopped may respond to antidepressants.

Cognitive-behavioral therapy (a form of psychotherapy) is effective in some patients. There are no other proven treatments for rehabilitation and maintenance after detoxification.

Methylenedioxymethamphetamine (Ecstasy, MDMA)

MDMA (3,4-methylenedioxymethamphetamine) is an amphetamine analog with stimulant and hallucinogenic effects.

MDMA acts primarily on neurons that produce and release serotonin, but it also affects dopaminergic neurons. MDMA is usually taken as a pill; effects begin 30 to 60 min after ingestion and typically last 4 to 6 h. MDMA is often used at dance clubs, concerts, and rave parties.

Symptoms and Signs

MDMA causes a state of excitement and disinhibition and accentuates physical sensation, empathy, and feelings of interpersonal closeness. Toxic effects are similar to those of the other amphetamines but are less common, perhaps because use is more likely to be intermittent. However, even with casual use, significant problems such as hyperthermia and centrally mediated hyponatremia may occur. The effects of intermittent, occasional use are uncertain. Rarely, fulminant hepatic failure occurs.

Chronic, repeated use may cause problems similar to those of amphetamines, including dependence. Some users develop paranoid psychosis. Cognitive decline may also occur with repeated, frequent use.

Diagnosis

MDMA may not be detected by routine urine immunoassay drug screens.

Treatment

Treatment for acute toxicity and dependency is similar to that for amphetamines, although treatment for acute overdose is less commonly needed.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • DESOXYN
  • DEXEDRINE
  • CONCERTA, RITALIN
  • LEVOPHED
  • No US brand name
  • DIPRIVAN
  • LOPRESSOR, TOPROL-XL
  • ATIVAN
  • NITROPRESS

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