Amphetamine Toxicity

Updated: May 30, 2020
  • Author: Neal Handly, MD, MS, MSc; Chief Editor: Jeter (Jay) Pritchard Taylor, III, MD  more...
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Overview

Practice Essentials

Amphetamines are a class of compounds that are abused in many regions of the world, including the United States, Australasia, and Europe. Synthetic amphetamine compounds commonly are produced in clandestine laboratories and vary in purity and potency. Other potentials for amphetamine abuse include prescription medications often used for attention deficit disorder and various over-the-counter diet pills.

Clinical effects of amphetamine abuse are significant and commonly observed in emergency departments (EDs). [1] Hendrickson et al, found that about 2.4% of visits at their institution were related to methamphetamphetamine use and annual estimated hospital charges of $6.9 million. [2] Patients may present with a range of psychiatric and medical problems, including agitation, psychosis, seizures, and potentially life-threatening cardiac dysrhythmias; see Presentation, Workup, and Treatment.

See also Methamphetamine Toxicity and MDMA Toxicity.

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Pathophysiology

Amphetamines are a group of structurally related compounds that produce central nervous system (CNS) and peripheral nervous system (PNS) stimulation. The phenylethylamine structure of amphetamines (see the image below) is similar to catecholaminergic, dopaminergic, and serotonergic agonists (biogenic amines), which may explain their actions.

Amphetamine and epinephrine. Amphetamine and epinephrine.

The degree to which an amphetamine can stimulate the receptors of these biogenic amines depends on the chemical substituents on the amphetamine molecule; thus, the clinical presentation depends on the type of amphetamine used. For example, methamphetamine lacks much of the peripheral stimulant properties of amphetamine while still offering euphoric and hallucinogenic properties. These actions are similar to those of cocaine; however, while effects of cocaine last for 10-20 minutes, duration of amphetamine action is much longer—as long as 10-12 hours.

The routes of amphetamine administration may be oral (ingestion), inhalation (smoke), or injection (intravenous). Oral use is associated with an approximate 1-hour lag time before onset of symptoms, whereas inhaled and intravenous methods yield effects within a few minutes. Peak plasma concentrations occur in 5 minutes with intravenous use, 30 minutes with nasal or intramuscular use, and 2-3 hours postingestion.

Use appears to vary with gender and race. Research has found correlations between personality traits (risk taking and reward sensitivity) and responses to amphetamine use. [3]

Central nervous system

Amphetamine compounds cause a general efflux of biogenic amines from neuronal synaptic terminals (indirect sympathomimetics). They inhibit specific transporters responsible for reuptake of biogenic amines from the synaptic nerve ending and presynaptic vesicles. Amphetamines also inhibit monoamine oxidase, which degrades biogenic amine neurotransmitters intracellularly. The net effect is an increase of neurotransmitter release into the synapse. Physiological adaptation occurs through receptor or coupling down-regulation; this tolerance and an accompanying psychological tolerance [4] can lead to escalating use of the drug and increased toxicity. [5] Long-term use can lead to a depletion of biogenic amine stores and a paradoxical reverse effect of the drug—a wash out.

Elevated catecholamine levels usually lead to a state of increased arousal and decreased fatigue. Increased dopamine levels at synapses in the CNS may be responsible for movement disorders [6] , schizophrenia, and euphoria. Serotonergic signals may play a role in the hallucinogenic and anorexic [7] aspects of these drugs.

Other serotonergic and dopaminergic effects may include resetting the thermal regulatory circuits upward in the hypothalamus and causing hyperthermia. The hyperthermia produced by amphetamines is similar to that of the serotonin syndrome.

Laboratory studies reveal that amphetamines interfere with the normal control of the neurohumoral (hypothalamopituitary) axis, affecting secretion of such factors as adrenocorticotropic hormone (ACTH). Amphetamines may alter other neural functions such as complex behavioral and learning patternings; this may be important for understanding effects of amphetamine use on the fetus during pregnancy.

Animal studies indicate that amphetamines interact with N-methyl-D-aspartate (NMDA) receptors on serotonergic neurons, leading to neuronal destruction. This interaction may contribute to seizure activity.

In vitro, amphetamines have been found to stimulate regulatory molecules, such as the oncogenes c-fos and ras and cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein. Amphetamines have been found to act on  ras mediated striatal motor control (insert ref). These proteins are responsible for signaling long-term changes at the transcriptional level.

Cardiovascular

Catecholaminergic (sympathomimetic) effects of amphetamines include inotropic and chronotropic effects on the heart, which can lead to tachycardia and other dysrhythmias. The vasoconstrictive properties of the drugs can lead to hypertension and/or coronary vasospasm. [8]

Serotonergic action of amphetamines on peripheral vasculature can lead to vasoconstriction, which is especially problematic in placental vessels. Animal studies have shown that serotonergic actions of amphetamines effect changes in plasma levels of oxytocin, somatostatin, gastrin, and cholecystokinin. [9]

Long-term use of the drugs can lead to myonecrosis and dilated cardiomyopathy. [10, 11] Amphetamine use is also associated with myocardial infarction [12]

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Etiology

Marked tolerance develops after amphetamine use and leads to rapid escalation of drug doses. Increasing the dose produces increasing toxicity and complications from acute and chronic amphetamine use.

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Epidemiology

Frequency

United States

Accurate estimation of illicit amphetamine use is difficult. An estimated 13 million Americans use these compounds without medical supervision. Random toxicologic screens performed in the ED indicate amphetamine presence in about 2% of patients. The 2018 Annual Report of the American Association of Poison Control Centers' National Poison Data System noted 10,027 single exposures with 1689 moderate outcomes, 125 major outcomes and 2 deaths. [13]

According to National Institute on Drug Abuse estimates for 2018, 3.7% of 8th graders, 5.7% of 10th graders, and 5.5% of 12th graders had used amphetamines during the past year. [14] Self-reporting among college students indicates an approximate 4% prevalence. An aged-matched survey of fourth-year medical students revealed that about 1.2% use amphetamines. It is unclear how many of these uses are of amphetamine-containing prescriptions for attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD). 

International

According to the United Nations Office on Drugs and Crime (UNODC)  World Drug Report 2018, global seizures of amphetamine in 2016 rose 20% from the previous year, with increasing seizures reported in parts of Central America, southeastern Europe, and southwestern Asia. [15]  However, a survey of students at institutes for higher education in Belgium found no change in the pattern of amphetamine use from 2005 to 2013. [16] The UNODC estimates that worldwide, there were 34 million users of amphetamines and prescription stimulants in 2018. [15]

Race- and sex-related demographics

Amphetamine use characteristically occurs among single white men aged 20-35 years who are typically unemployed. [17] Data from rural populations reveal that whites use amphetamines significantly more than blacks . [18] However, amphetamine use is becoming more common among women and other ethnic groups.

One study suggests that the action of estrogen within the CNS might explain why fewer women than men use amphetamines. Women in their late follicular phase (when estrogen levels are high and progesterone levels are low) were more likely to report "unpleasant stimulation" when exposed to amphetamine. This effect was not observed in the early follicular phase, when both hormone levels are low. [19]

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Prognosis

Patients without signs or symptoms of end-organ failure or infections may do well with sedation and reassurance. No established modalities exist for treatment of amphetamine addiction.

Hyperthermia accompanies and complicates significant amphetamine intoxication. Liver damage apparently is linked to elevated body temperature and consumption of reduced glutathione in metabolism of amphetamines. Because amphetamines often are synthesized in poorly controlled settings, individuals with amphetamine intoxication may experience concomitant toxic exposures.  Lead, other metals, organic solvents, and precursor molecules all have been found in amphetamine samples and blood of individuals with amphetamine toxicity.

Acute overdose of amphetamines can result in the following:

  • Seizures
  • Hypertension
  • Tachycardia
  • Myocardial infarction [20]
  • Hyperthermia
  • Psychosis [21]
  • Hallucinosis
  • Stroke
  • Death

Habitual amphetamine use produces toxic psychosis resembling paranoid schizophrenia. Hallucinations, delusions, and bizarre violent behavior are common. In a few patients, amphetamine use produces long-term paranoid schizophrenia; whether this results from unmasking underlying disease is unclear. Severe psychological depression and prolonged sleep follow chronic use and binges.

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Patient Education

Educate patients on the toxic effects of amphetamines and that amphetamines are not a safe alternative to cocaine use. For patient education information, see the First Aid and Injuries Center and Mental Health Center, as well as Drug Dependence & AbusePoisoningClub DrugsActivated Charcoal, and Substance Abuse.

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