History and exam

Key diagnostic factors

common

presence of risk factors

Significant risk is imparted by exposure to high temperature, exercise, sweating, volume depletion, attendance at dance club or rave party, polydrug and alcohol usage, anxiety, depression, behavioural deviation or criminality, and ADHD.[31][32]

agitation, irrationality, restlessness, sometimes aggressive behaviour

Due to sympathetic over-stimulation.[23][38][39][59] May require immediate sedation to conduct an exam.

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

Rectal temperature most closely approximates core body temperature. Any temperature >38°C (>100°F) requires active cooling measures.[4][5][7][19][28]

hyperthermia >39.5°C (>103°F)

Indicates severe, potentially life-threatening toxicity and mandates immediate cooling and sedation.[4][5][7][19][28]

seizures

Suggests haemodilution, intracranial haemorrhage or injury, hyponatraemia 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 over-stimulation.[23][38][39]

traumatic injury

Common in misuse of amfetamines and may complicate the clinical picture and management.[60]

headache

May indicate intracranial oedema or intracranial haemorrhage.[2][3]

serotonin drug interaction

Common prescription medications that interact adversely: serotonin-reuptake inhibitors (e.g., tramadol, metoclopramide, sumatriptan, lithium, dextromethorphan).[29][47]

hypertension

Due to sympathetic over-stimulation, amfetamine-induced release of catecholamines.[23][38][39][61]

hyperreflexia and clonus

Due to sympathetic over-stimulation. Associated with serotonin toxicity.[29][47]

uncommon

chest pain

May indicate myocardial ischaemia, very seldom infarction.[49]

cardiac arrhythmia

Death from cardiac arrhythmia has been reported in amfetamine toxicity, usually in presence of pre-existing ischaemic heart disease.[39][49]

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 over-stimulation.

disorientation, confusion, delirium

Altered level of consciousness is consistent with amfetamine 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 over-stimulation.

hallucinations or delusions

May occur with use of amfetamines without toxicity, but is more common in toxic doses.[9][23][38][62]

tremor, hypertonicity, or muscle rigidity

Parkinsonism may be seen with chronic misuse of amfetamines.[63] Rigidity may indicate serotonin toxicity.[47]

paranoia, hypervigilance, or psychosis

May require behavioural control by physical restraint or injectable drugs before specific treatment of amfetamine overdose.

mydriasis

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

uncommon

history of heart disease

Pre-existing ischaemic heart disease has been associated with reports of death from amfetamine-related toxicity.[26]

tachypnoea

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

dyspnoea

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.[51]

abdominal pain

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

positive Babinski reflex

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

focal neurological signs, papilloedema

Subarachnoid haemorrhage is an unusual presentation in overdose of amfetamines.

Risk factors

strong

high ambient temperature

3,4-methylenedioxymethamfetamine (MDMA or ecstasy) inhibits thermoregulation, leading to hyperthermia. The effect is pronounced in hot environments and is dose-dependent.[4][5][7][19][28]

volume depletion

Stimulants may mask thirst and decrease fluid consumption.[7][19]

exercise and sweating

Contributes to hyperthermia and volume depletion.[7][19]

excessive alcohol intake

Chronic or high intake may potentiate the effects of amfetamines. Also contributes to volume depletion.[19][20]

polydrug usage

Multiple substance misuse is common, including prescription medications, and should be inquired about specifically.[19][20][29]

anxiety and depression

People with underlying psychiatric disorders may be susceptible to the euphoric effects of amfetamines and increase dose without discretion.[30]

history of behavioural disturbance

So-called high-risk or abusive behaviours increase risk of amfetamine misuse.[31]

history of delinquency or crime

Past conviction of juvenile criminal offence increases risk of amfetamine misuse.[32][33]

ADHD

Two in 10 youths with ADHD misuse their stimulant medications.[32]

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 amfetamine 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][34][35][36][37]

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