Amphetamine Toxicity

Amphetamine toxicity follows overdose or misuse of amphetamine, dexamfetamine, methamphetamine and methylenedioxymethamphetamine (MDMA, ecstasy). The drugs enter nerve terminals through transporters and reverse them, releasing dopamine, noradrenaline and serotonin, and they inhibit monoamine oxidase. Methamphetamine and amphetamine have half-lives of 10 to 12 hours, and MDMA 7 to 9 hours. Effects therefore last far longer than cocaine.

Therapeutic dexamfetamine doses are 5 to 60 mg a day. In a drug-naive adult, doses over 1 mg/kg cause moderate toxicity, and deaths occur from about 5 mg/kg, and far less in children. Tolerant users survive much higher doses.

Toxicity patterns

• Sympathomimetic: agitation, hypertension, tachycardia, hyperthermia
• MDMA: hyponatremia from vasopressin release and excess water intake, serotonin toxicity and hepatotoxicity
• Chronic methamphetamine use: cardiomyopathy, pulmonary hypertension, dental decay, skin picking, weight loss, persistent psychosis and cognitive decline

Complications: hyperthermia with rhabdomyolysis and disseminated intravascular coagulation, intracranial hemorrhage, myocardial infarction, aortic dissection, seizures, cerebral edema from hyponatremia, acute kidney injury and liver failure.

• Agitation, paranoia, hallucinations, dilated pupils, sweating, bruxism, tremor and hyperreflexia
• Tachycardia, hypertension, chest pain and arrhythmia
• Temperature over 38.5 degrees Celsius, muscle rigidity and dark urine
• MDMA: headache, confusion, seizures from hyponatremia, and clonus with serotonin toxicity
• Chronic use: weight loss, skin sores, severe dental decay and persistent psychosis
• Red flags: temperature over 40 degrees Celsius, sodium under 125 mmol/L, seizures, severe headache with focal deficit and chest pain

1. Clinical diagnosis, with immediate checks: temperature, blood pressure, heart rate, glucose and neurological state.
2. Laboratory tests: sodium (repeat every 2 hours for MDMA), potassium, creatinine, creatine kinase, liver tests, lactate, coagulation studies and blood gases.
3. ECG and troponin, and CT head for severe headache, focal signs or reduced consciousness.
4. Urine amphetamine immunoassay (positive for 2 to 4 days) with confirmatory mass spectrometry, since false positives occur with some drugs.
5. Echocardiography for chronic users with breathlessness or edema.

Differentials: cocaine and cathinone toxicity, serotonin syndrome, thyrotoxicosis, neuroleptic malignant syndrome, alcohol withdrawal, sepsis, primary psychosis.

1. Benzodiazepines first: lorazepam 2 to 4 mg IV (children 0.05 to 0.1 mg/kg) or diazepam 5 to 10 mg IV (children 0.1 to 0.2 mg/kg), repeated every 5 to 10 minutes until calm. Monitor respiration.
2. Resistant agitation or psychosis: olanzapine 5 to 10 mg orally or IM (maximum 20 mg in 24 hours) or haloperidol 5 mg IM. Antipsychotics lower the seizure threshold and worsen hyperthermia, so use them only after benzodiazepines and check QTc.
3. Hyperthermia: rapid external cooling to under 38.5 degrees Celsius. For temperature over 41 degrees Celsius, intubate and paralyze with rocuronium 1 mg/kg IV. Avoid succinylcholine, which risks hyperkalemia. Dantrolene is not recommended.
4. Hypertension: benzodiazepines, then phentolamine 1 to 5 mg IV or sodium nitroprusside 0.5 to 10 micrograms/kg/min IV. Avoid beta blockers.
5. Chest pain: aspirin 300 mg chewed once, glyceryl trinitrate 0.4 mg sublingually every 5 minutes up to 3 doses, and the acute coronary syndrome pathway.
6. MDMA hyponatremia: restrict fluids to 800 mL a day. For seizures or sodium under 125 mmol/L give 3% saline 100 mL IV over 10 minutes (children 2 mL/kg), repeated up to 3 times, with sodium every 2 hours. Do not raise sodium faster than 8 mmol/L in 24 hours. Avoid hypotonic fluids.
7. Serotonin toxicity: cyproheptadine 12 mg orally then 2 mg every 2 hours, with maintenance 8 mg every 6 hours (maximum 32 mg a day).
8. Seizures: benzodiazepines. Avoid phenytoin.
9. Rhabdomyolysis: IV 0.9% saline 200 to 300 mL/h to keep urine output over 1 mL/kg/h. Disseminated intravascular coagulation: fresh frozen plasma 15 mL/kg for bleeding with prolonged clotting times.
10. Decontamination: activated charcoal 50 g (children 1 g/kg) within 1 to 2 hours of a large ingestion with a protected airway.
11. Observation: at least 6 hours with normal vital signs, and 8 hours for MDMA with a sodium check before discharge.
12. Methamphetamine use disorder: contingency management and cognitive behavioral therapy. Extended-release naltrexone 380 mg IM every 3 weeks with bupropion extended-release 450 mg orally daily for 12 weeks reduces use. Persistent psychosis responds to olanzapine 5 to 10 mg orally daily for 2 to 4 weeks. Cardiomyopathy needs ramipril 2.5 mg orally daily, increased to 10 mg, and carvedilol started once abstinent.

Follow-up for blood pressure and psychosis at 2 weeks, screening for HIV and hepatitis, and counseling on harm reduction.