History and exam

Key diagnostic factors

common

agitation, irrationality, restlessness, sometimes aggressive behavior

Due to sympathetic overstimulation.[21][36][37][57] May require immediate sedation to conduct an exam.

hyperthermia >100°F (>38°C) but <103°F (<39.5°C)

Rectal temperature most closely approximates core body temperature. Any temperature >100°F (>38°C) requires active cooling measures.[4][5][7][17][26]

hyperthermia >103°F (>39.5°C)

Indicates severe, potentially life-threatening toxicity and mandates immediate cooling and sedation.[4][5][7][17][26]

seizures

Suggests hemodilution, intracranial hemorrhage or injury, hyponatremia from excessive water drinking to counter thirst, volume depletion.

diaphoresis, flushed facial skin

Due to hyperthermia, excessive sympathetic stimulation. May be the first clue of psychostimulant toxicity.

tachycardia and palpitations

With or without arrhythmias, requires ECG to evaluate. Due to sympathetic overstimulation.[21][36][37]

traumatic injury

Common in misuse of amphetamines and may complicate the clinical picture and management.[58]

headache

May indicate intracranial edema or intracranial hemorrhage.[2][3]

serotonin drug interaction

Common prescription medications that interact adversely: serotonin-reuptake inhibitors (e.g., tramadol, metoclopramide, sumatriptan, lithium, dextromethorphan).[27][45]

hypertension

Due to sympathetic overstimulation, amphetamine-induced release of catecholamines.[21][36][37][59]

hyperreflexia and clonus

Due to sympathetic overstimulation. Associated with serotonin toxicity.[27][45]

uncommon

chest pain

May indicate myocardial ischemia, very seldom infarction.[47]

cardiac arrhythmia

Death from cardiac arrhythmia has been reported in amphetamine toxicity, usually in presence of pre-existing ischemic heart disease.[37][47]

Other diagnostic factors

common

history of hepatitis B or C, HIV

May indicate a long-standing history of substance misuse, high-risk lifestyle.

tremor, repetitive movements

Due to sympathetic overstimulation.

disorientation, confusion, delirium

Altered level of consciousness is consistent with amphetamine toxicity.

malnutrition

Obvious signs of poor nutrition, open sores, muscle wasting, poor dentition, associated with long-standing history of substance misuse.

superficial venous abnormalities

Evidence of needle marks or thrombophlebitis may indicate long-standing drug use.

rapid speech, pacing, trismus

Due to sympathetic overstimulation.

hallucinations or delusions

May occur with use of amphetamines without toxicity, but is more common in toxic doses.[9][21][36][60]

tremor, hypertonicity, or muscle rigidity

Parkinsonism may be seen with chronic misuse of amphetamines.[61] Rigidity may indicate serotonin toxicity.[45]

paranoia, hypervigilance, or psychosis

May require behavioral control by physical restraint or injectable drugs before specific treatment of amphetamine overdose.

mydriasis

Pupil dilation with sluggish reaction to light, from sympathetic stimulation.

uncommon

history of heart disease

Pre-existing ischemic heart disease has been associated with reports of death from amphetamine-related toxicity.[24]

tachypnea

May present as hyperventilatory response to acidosis or as finding in acute respiratory distress syndrome.

dyspnea

Respiratory symptoms may reflect cardiovascular compromise such as myocardial strain or heart failure.

lack of thirst

Paradoxical finding, as stimulants may mask thirst and actually decrease fluid consumption, exacerbating volume depletion.[49]

abdominal pain

May indicate vasculitis or mesenteric ischemia, ingested packets of drug, obstruction.

positive Babinski reflex

Bilateral, typical of serotonin toxicity. Neuromuscular findings are more pronounced in lower extremities.

focal neurologic signs, papilledema

Subarachnoid hemorrhage is an unusual presentation in overdose of amphetamines.

Risk factors

strong

high ambient temperature

MDMA (ecstasy) inhibits thermoregulation, leading to hyperthermia. The effect is pronounced in hot environments and is dose-dependent.[4][5][7][17][26]

volume depletion

Stimulants may mask thirst and decrease fluid consumption.[7][17]

exercise and sweating

Contributes to hyperthermia and volume depletion.[7][17]

excessive alcohol intake

Chronic or high intake may potentiate the effects of amphetamines. Also contributes to volume depletion.[17][18]

polydrug usage

Multiple substance misuse is common, including prescription medications, and should be inquired of specifically.[17][18][27]

anxiety and depression

People with underlying psychiatric disorders may be susceptible to the euphoric effects of amphetamines and increase dose without discretion.[28]

history of behavioral disturbance

So-called high-risk or abusive behaviors increase risk of amphetamine misuse.[29]

history of delinquency or crime

Past conviction of juvenile criminal offense increases risk of amphetamine misuse.[30][31]

ADHD

Two in 10 youths with ADHD misuse their stimulant medications.[30]

attendance at dance club or rave party

Use of MDMA (ecstasy) and related drugs is common in this environment.

weak

history of drug misuse for >1 year

Weakly linked to amphetamine overdose.

genetic predilection

Absence of the P450 cytochrome oxidase CYP2D6 gene is postulated to be a risk factor for drug-induced hepatotoxicity and heart failure, but a definitive clinical link is not yet established.[8][32][33][34][35]

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