Amphetamine Toxicity

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.

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]

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.

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 2019 Annual Report of the American Association of Poison Control Centers' National Poison Data System noted 10,222 single exposures with 1769 moderate outcomes, 180 major outcomes and 6 deaths.[13]

According to National Institute on Drug Abuse estimates for 2020, 5.3% of 8th graders, 5.7% of 10th graders, and 4.3% 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 2021, global seizures of amphetamine reached a record high in 2019, with 49% of seizures in the Near and MIddle East/South-West Asia. Western and Central Europe accounted for 26% of seizures. The UNODC estimates that worldwide, there were 27 million users of amphetamines and prescription stimulants in 2019.[15]

Race- and sex-related demographics

Amphetamine use characteristically occurs among single white men aged 20-35 years who are typically unemployed.[16] Data from rural populations reveal that whites use amphetamines significantly more than blacks .[17] 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.[18]

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 ^[19]
• Hyperthermia
• Psychosis ^[20]
• 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.

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 & Abuse, Poisoning, Club Drugs, Activated Charcoal, and Substance Abuse.

Many patients with amphetamine intoxication are identified by a change of mental status alone. In other cases, the mental status change is associated with another injury and/or illness. Trauma often accompanies amphetamine intoxication and should be sought in the evaluation of the patient.

Central nervous system manifestations are as follows:

• Change of mental status, disorientation, and headache
• Dyskinesias
• Agitation
• Formication
• Symptoms of stroke

Cardiovascular manifestations are as follows:

• Chest pain
• Palpitations

Gastrointestinal manifestations are as follows:

• Dry mouth
• Nausea and vomiting
• Diarrhea

Skin/cutaneous manifestations are as follows:

• Diaphoresis
• Erythematous painful rashes, needle marks
• Infected deep ulcerations (ecthyma)

Genitourinary (GU) manifestations include difficult micturition. Ocular manifestations include mydriasis.

Physical examination findings may demonstrate the strong central nervous system and peripheral nervous system stimulation produced by amphetamine compounds. Hyperthermia accompanies and complicates significant amphetamine intoxication.[21]  Modification of the basic amphetamine molecule produces compounds with variable effects on target organs. Methamphetamine produces prominent central nervous system effects with minimal cardiovascular stimulation.

Long-term users of intravenous amphetamines are at risk of infection and vascular injury.

General findings are as follows:

• Weight loss
• Hyperactivity, confusion, and agitation (may combine to produce severe hyperthermia, which can be worse in physically restrained individuals)
• Diaphoresis
• Mydriasis
• Anorexia

Cardiovascular findings are as follows:

• Alpha- and beta-adrenergic stimulation can lead to systolic and diastolic blood pressure increases
• Heart rate may be unchanged or slow in response to hypertension
• Increasing doses produce tachycardia and other dysrhythmias, including ventricular tachycardia and fibrillation
• Hypertensive crisis or vasospasm may lead to stroke

Central nervous system findings are as follows:

• Increased alertness
• Euphoria
• Confusion or agitation
• Bruxism
• Stroke caused by acute amphetamine toxicity

Cutaneous findings are as follows:

• Skin flushing
• Infected deep ulcerations (ecthyma) in patients with formication
• Skin track marks, cellulitis, abscesses, phlebitis, or vasculitis with intravenous use

Other organ system findings are as follows:

• Respiratory distress secondary to acute lung injury (ALI), in patients who smoke amphetamines
• Gastrointestinal - Nausea or vomiting
• Dental - "Meth mouth," a condition of eroded teeth

Patients with amphetamine intoxication who present with no life-threatening signs or symptoms may be treated with sedation and observation and may require no laboratory workup.

Patients who are experiencing seizures or prolonged mental status changes require rapid serum glucose determination (eg, fingerstick) and electrolyte testing.

Patients with suicidal ideations should have serum acetaminophen level checked.

Evaluate renal and hepatic function of patients who are demonstrating significant or prolonged hyperthermia and search for infectious causes.

When appropriate, evaluation may include urinalysis, urine culture, blood culture, spinal fluid analysis and staining, and culture of material from cutaneous sources.

Because hyperthermia may induce disseminated intravascular coagulation (DIC), monitor for DIC and treat appropriately if it occurs.

Obtain urine and serum creatinine kinase levels to monitor for rhabdomyolysis. If the dipstick result is positive for blood but shows few or no red blood cells on microscopic examination, rhabdomyolysis may be present.

Urine specimens for drug and toxicologic screens may be collected after Foley catheter placement if the physician believes that these tests will help guide therapy.

Usually, the presence of pure sympathomimetic toxidrome precludes the need for drug screening. However, with methamphetamine and other designer amphetamines, peripheral effects may not be observed.

Patients who are demonstrating only mild symptoms from amphetamine intoxication often respond to sedation and recover rapidly under observation. Such patients require no imaging studies unless trauma is suspected.

Obtain a chest radiograph for patients complaining of chest pain or respiratory distress. Obtain a CT scan of the head for patients with recurrent seizures or prolonged mental status changes if no metabolic cause can be quickly found and corrected.

Look for infectious causes in patients who are demonstrating significant or prolonged hyperthermia; this may include chest radiography, echocardiography, CT of the head and abdomen, and extremity ultrasonography of suspected abscesses.

Perform electrocardiographic testing and monitor patients complaining of chest pain. Obtain appropriate cardiac enzyme testing if pain is prolonged or cardiac injury is suspected.

A lumbar puncture (LP) should be performed in hyperthermic patients with altered mental status, where CNS infection cannot be excluded.

Prehospital care of patients with amphetamine intoxication often requires physical and chemical restraint of the patient and treatment of complications of intoxication, including seizures, loss of competent airway, cardiac dysrhythmias, and trauma.

Patients with amphetamine intoxication who present with no life-threatening signs or symptoms may be treated with sedation and observation. Complications may require the physician to perform procedures to establish airway management or fluid resuscitation or to initiate vigorous cooling measures.

In patients with acute oral ingestion, gastrointestinal (GI) decontamination is performed by the administration of activated charcoal. Orogastric lavage often is not necessary but may be performed when the patient presents with immediately life-threatening intoxication shortly after ingestion. Whole-bowel irrigation may be indicated in suspected cases of body stuffing or body packing (large quantities of drugs in wrapping for international transport or drug hiding, respectively).

Foley catheter placement may be useful to monitor urine output, particularly in situations in which diuretics are administered to manage pulmonary edema. Patients often have decreased urination due to the effects on bladder sphincter muscles. Other individuals may be dehydrated after recreational use in raves and club events. Quick assessment of bladder fullness can be performed with bedside ultrasonography or bladder palpation.

Agitation or persisting seizures in patients with amphetamine toxicity requires generous titration of benzodiazepines and a calm soothing environment. Avoid physical restraints, if possible.

Significant cardiac dysrhythmias may require cardioversion, defibrillation, and antidysrhythmics. Prolonged hypertension may present a cardiovascular risk. Use benzodiazepine sedation (nonspecific sympatholysis) to initially manage hypertension, if present. Refractory cases or cases associated with significant end-organ toxicity (eg, cardiovascular accident [CVA], myocardial ischemia) can be managed with intravenous phentolamine, nitroprusside, or nitroglycerin.

Avoid use of beta-blockers in order to prevent unopposed alpha effect (vasoconstriction). Note that combination alpha-adrenergic and beta-adrenergic antagonists may play a valuable role in managing tachycardias; this recommendation is based on class IIb evidence in the revision of unstable angina/non-ST segment elevation myocardial infarction guidelines by the American Heart Association (based on similarities of amphetamine and cocaine toxicities).[29]

Cardiogenic pulmonary edema can be managed with nitroglycerin and diuretics.

Aggressively cool hyperthermic patients with evaporative cooling, ice packs to the groin and axilla, and use of "ice-bath" (total body immersion in ice). Patients with severe hyperthermia (temperature >104°F) associated with psychomotor agitation may require immediate neuromuscular paralysis to rapidly decrease temperature. Temperature control should be achieved within 15-20 minutes upon presentation in order to prevent multiorgan failure and death.

Haloperidol is controversial in the treatment of agitation in any patient with the potential to seize or develop hyperthermia because of associations with lowering the seizure threshold and altering thermoregulation.[30] Of all neuroleptic drugs, however, haloperidol rarely is associated with seizures (minimal effects on seizure threshold). In addition, animal studies suggest that haloperidol can antagonize amphetamine-induced hyperthermia. Haloperidol can be considered as an adjunct to benzodiazepines for afebrile patients with normal vital signs and psychomotor agitation that requires chemical restraint.

Treat rhabdomyolysis with generous intravenous fluids alkalinized with sodium bicarbonate, control of agitation, and temperature normalization.

Look for and treat traumatic injuries in patients with amphetamine intoxication.

Admission is appropriate for monitoring and treatment of the following severe sequelae of amphetamine use:

• Unstable vital signs (eg, hypertension, hyperthermia) and tachycardia or other dysrhythmias
• Chest pain, to rule out myocardial infarction
• Respiratory distress, pulmonary edema
• Neurologic and neurosurgical complications, status epilepticus, coma, and cerebral hemorrhage or  ischemic stroke
• Psychiatric intervention for persistent toxic psychosis or drug detoxification program entry

A patient with stable vital signs who exhibits paranoid psychosis and has no evidence of cardiac, cerebral, renal, hepatic, or pulmonary complications of amphetamine use may need to be transferred to a psychiatric hospital for observation and treatment.

 

A medical toxicologist may be consulted for assistance in the management of amphetamine toxicity cases. Patients who demonstrate focal neural deficits or have CT scans of the head that indicate bleeding may need neurologic or neurosurgical consultations. Patients who show significant cardiac injury may require cardiologic consultation.

Patients may need referral for outpatient detoxification centers or for management of addictive behaviors.

Medications available for amphetamine toxicity include gastric decontaminants (charcoal with or without sorbitol), sedatives to control CNS stimulation caused by amphetamines (benzodiazepines, antipsychotics), muscle relaxants (benzodiazepines, dantrolene), and several drugs to control possible hemodynamic cardiovascular disturbances (alpha-adrenergic blockers, nitrates, diuretics).

Class Summary

These agents are used to adsorb amphetamine after acute ingestion and to limit absorption into systemic circulation. Limited utility beyond 4 h of ingestion, unless the patient ingested sustained-release formulation or is suspected of being a body packer (ie, ingestion of a large amount of drug in a plastic bag or condom to smuggle or avoid arrest). Charcoal is not beneficial for other routes of exposure (eg, IV, inhalation or injection). Clinician should be aware of potential risk of charcoal aspiration and death due to aspiration pneumonia, especially in patients with altered mental status and/or having seizures. Prudent airway control is recommended in such population.

Activated charcoal

Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

For maximum effect, administer within 30 min of ingestion of poison. May administer as aqueous suspension or combine with cathartic (usually sorbitol 70%) in the presence of active bowel sounds.

Repeat dose, if necessary (without cathartic), to adsorb large pill masses or drug packages.

With superactivated forms, use of doses of 0.5 g/kg PO may be possible.

Class Summary

These agents are important for sedation counteracting the CNS and PNS excitation of amphetamines. A benzodiazepine is generally considered as the first agent of choice for hypertension and agitation, in addition to their utility for treating seizures.

Lorazepam (Ativan)

Beneficial for sedative and anticonvulsant effects. In addition, the calming effects may prove beneficial for the adverse cardiovascular effects (eg, hypertension, tachycardia) of amphetamines.

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Third-line agent for agitation or seizures because of shorter duration of anticonvulsive effects and accumulation of active metabolites that may prolong sedation.

Midazolam (Versed)

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to evaluate sedative effects fully before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.

Class Summary

Antipsychotics are used to manage psychosis, agitation, and hyperthermia that may result from amphetamine use.

Haloperidol (Haldol)

DOC for patients with acute psychosis when no contraindications exist. Noted for high potency and low potential for causing orthostasis. Downside is the high potential for EPS (dystonia) and lowering the seizure threshold.

Use in acute amphetamine toxicity is controversial. If haloperidol is being considered, administer a benzodiazepine first. May then be used as adjunctive therapy to control agitation in afebrile patients with normal vital signs.

Parenteral dosage form may be admixed in syringe with 2 mg lorazepam for better anxiolytic effects.

Class Summary

These agents are used to control or reverse hyperthermic effects. Most hyperthermia is mediated by neuromuscular agitation.

Dantrolene (Dantrium)

Has been used successfully in isolated case reports to control hyperthermia; however, efficacy has not been established for amphetamine-associated hyperthermia. Reverse of hyperthermic effects may take several hours. Because morbidity and mortality from hyperthermia is closely correlated with severity and duration of hyperthermia, aggressive cooling (eg, ice bath) and agents that work more readily to reverse hyperthermia are preferred over dantrolene.

Class Summary

Alpha- and beta-adrenergic antagonists control peripheral vasoconstriction that results from sympathetic stimulation due to amphetamines. Treating with a beta-blocker to control the heart rate will leave unopposed alpha activity that can cause vasoconstriction. Combination alpha- and beta-adrenergic antagonists, such as labetalol, may have therapeutic value. Alpha-adrenergic antagonists specifically may be used to treat severe headache, SAH, cardiac ischemia, and hypertension associated with amphetamines. Use nitrates to control vasoconstriction and hypertensive emergency.

Labetalol

Blocks beta1-, alpha-, and beta2-adrenergic receptor sites decreasing blood pressure.

Phentolamine (Regitine)

Alpha1- and alpha2-adrenergic blocking agent that blocks circulating epinephrine and norepinephrine action, reducing hypertension that results from catecholamine effects on the alpha-adrenergic receptors.

Nitroprusside (Nitropress)

Produces vasodilation and increases inotropic activity of the heart. May exacerbate myocardial ischemia at higher doses by increasing heart rate.

Nitroglycerin IV (Deponit, Nitro-bid, Nitrostat)

Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. The result is a decrease in blood pressure. Valuable for controlling cardiac pain and pulmonary edema.

May administer bolus of 12.5-25 mcg or give a 400-mcg tab SL as a bolus before continuous infusion.

Initial infusion rate of 10-20 mcg/min may be increased 5-10 mcg/min q5-10min until desired clinical or hemodynamic response is achieved. Infusion rates of 500 mcg/min occasionally have been required.

Class Summary

These agents are used to control and treat pulmonary edema and could be beneficial in a hypertensive crisis.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system that, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.