Amphetamine Toxicity 

Amphetamines are a class of compounds increasingly abused in regions of the world such as the western 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 and various over-the-counter diet pills.

Clinical effects of amphetamine abuse are significant and commonly observed in EDs. The ED physician's ability to recognize and treat amphetamine intoxication is very important.

The phenylethylamine structure of amphetamines (see the image below) is similar to catecholaminergic, dopaminergic, and serotonergic agonists (biogenic amines), which may explain their actions.

The relative activities that amphetamines have to stimulate the receptors of these biogenic amines are dependent on the chemical substituents on the amphetamine molecule; thus, the clinical presentation is dependent 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, lasting 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. Recent work has found correlations between personality traits (risk taking and reward sensitivity) and responses to amphetamine use.^[1]

Amphetamines are a group of structurally related compounds that produce central nervous system (CNS) and peripheral nervous system (PNS) stimulation.

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^[2] can lead to escalating use of the drug and increased toxicity.^[3] Chronic 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^[4] , schizophrenia, and euphoria. Serotonergic signals may play a role in the hallucinogenic and anorexic^[5] 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 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. These proteins are responsible for signaling long-term changes at the transcriptional level.

Peripheral nervous system

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.^[6]

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.^[7]

Cardiovascular

Long-term use of the drugs can lead to myonecrosis and dilated cardiomyopathy.^[8] Amphetamine use is also associated with increased risk of pulmonary hypertension.^[9]

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. 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.

Locations of amphetamine drug factories may establish the regional nature of amphetamine use.^[10] Use of these drugs in the United States mostly occurs in the large cities of the southwest. Of all amphetamine drug factory busts, 75% have occurred in California, Texas, and Oregon. At UC Davis's ED in the late 1980s, the prevalence of amphetamine toxicity was found to be 0.69%.

Despite the large focus of use in the western United States during the 1980s, many episodes of methamphetamine complications occurred in Minneapolis and Philadelphia. Importation of amphetamines from the Far East fuels Hawaiian drug use. As of August 1999, amphetamine-producing laboratories have sprung up in Mexico; border city narcotics officers blame the more lucrative street valuation of methamphetamine in the United States compared with cocaine. Amphetamines then are imported through cities along the US-Mexico border for sale at prices up to $26,000 per kilogram (cocaine is approximately $14,000 per kilogram).

International

Amphetamine use has been found to be increasing in Europe. In 1993, in the Frankfurt area, 9% of reckless driving arrests were associated with amphetamine use.^[11] A study among adolescents in Taiwan found a prevalence of 2.7% and an estimated lifetime amphetamine use of about 4%.^[12] In the United Kingdom, the number of amphetamine confiscations by law enforcement is only exceeded by that of cannabis.

Ring methoxylated amphetamine compounds have been found in a number of autopsies performed in Europe. Whether these are contaminants or byproducts in the production of methylenedioxymethamphetamine (MDMA) preparations, also known as Ecstasy, is unclear. Neither amphetamine nor methamphetamine was found in the blood of these individuals, suggesting that amphetamines were not deliberately added in the compounding of these Ecstasy tablets.

Mortality/Morbidity

Acute overdose of amphetamines produces seizures, hypertension, tachycardia, hyperthermia, psychosis, hallucinosis, stroke, and fatality.

• One study at San Francisco General Hospital from 1975-1987 determined that approximately 25% of seizures were secondary to amphetamine use.^[13]
• 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.
• Habitual amphetamine use produces toxic psychosis resembling paranoid schizophrenia. Hallucinations, delusions, and bizarre violent behavior are common.
• Amphetamine use was associated with an increased risk of myocardial infarctions in 15-45 year olds in Texas.^[14]

Race

In the United States, amphetamine use characteristically occurs among single white men. Data from rural populations reveal that Caucasians use amphetamines significantly more than African Americans.^[15]

Sex

Amphetamine use characteristically occurs among single white men aged 20-35 years who are typically unemployed.^[16] However, amphetamine use is becoming more common among women and other ethnic groups.

A recent 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.^[17]