Amphetamines are stimulants with euphoriant properties that are used via various routes, including ingestion, injection, snorting, and smoking. Toxicity is caused by excess catecholamine release, presenting as hyperactive delirium or sympathomimetic toxidrome (agitation, delirium, hypertension, seizures, and hyperthermia) and causing ventricular dysrhythmias, rhabdomyolysis, kidney failure, and/or status epilepticus. Diagnosis is by history and physical examination and sometimes urine testing, with ECG to monitor for complications. Toxicity is managed with intravenous benzodiazepines for agitation, hypertension, and seizures, and cooling for hyperthermia. Psychosis and depression are potential psychiatric complications.
Amphetamines are part of a group of drugs that share a common chemical structure, alpha-methylphenethylamine. Phenethylamine is a benzene ring connected to an ethyl chain with an amine group at the end, which is the basic chemical structure for epinephrine, norepinephrine, and dopamine. The original drug in this class, amphetamine, has been modified by various substitutions on its phenyl ring, resulting in many variations, including methamphetamine, 3,4-methylenedioxymethamphetamine (Ecstasy, MDMA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), and numerous others. There is an illuminating relationship between the specific part of phenethylamine that is modified and the effects of the resulting chemical (1). Chemicals derived from modifying the ethylamine portion are more stimulatory (eg, amphetamine, methamphetamine, cathinone). Chemicals derived from modifying the phenyl ring are more hallucinogenic (eg, mescaline). Modifying both the phenyl and ethylamine regions leads to a mix of stimulatory and hallucinogenic effects (eg, MDMA). The original drug amphetamine is still in use as a prescription medication and as a drug of abuse.
Street names for amphetamines include Speed and Uppers. Street names for methamphetamine include Meth, Crystal Meth, Chalk, and Crank.
Some derivatives of amphetamine are used as therapeutic medications. Dextroamphetamine, methamphetamine, and methylphenidate are used to treat attention-deficit hyperactivity disorder and narcolepsy. The availability of prescription or over-the-counter amphetamine derivatives has the unintended effect of creating a supply that can be diverted for illicit use. The epidemiology of stimulant medication misuse is complex. Most research focuses on adolescents and college age adults in the United States using the medication for academic performance or to self-medicate for undiagnosed ADHD (2). In that group, approximately 1 person in 10 will misuse a prescription stimulant at least once.
Amphetamine derivatives have also been used as appetite suppressants. Phentermine alone and in combination with topiramate is available as an anorectic. Medications containing fenfluramine, dexfenfluramine, and fenfluramine were removed from the United States market in 1997 because of an association with valvular heart disease (3).
References
1. Glennon RA. The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse. J Med Chem. 2017;60(7):2605-2628. doi:10.1021/acs.jmedchem.7b00085
2. Carolan D. ADHD stimulant medication misuse and considerations for current prescribing practice: a literature review. Ir J Med Sci. 2022;191(1):313-320. doi:10.1007/s11845-020-02502-1
3. Jick H, Vasilakis C, Weinrauch LA, Meier CR, Jick SS, Derby LE. A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation. N Engl J Med. 1998;339(11):719-724. doi:10.1056/NEJM199809103391102
Pathophysiology of Amphetamine Use
Amphetamines enhance the release of norepinephrine, dopamine, and serotonin into the synaptic cleft. This leads to increased alertness, euphoria, and anorexia. Toxicity arises from excess catecholamine release, manifesting as hyperactive delirium or the sympathomimetic toxidrome (agitation, delirium, hypertension, seizures, and hyperthermia).
Illicit amphetamines usually are a powder and the most common routes of use are insufflation ("snorting") or injecting. Prescription amphetamines are usually pills that are crushed and then insufflated. Injecting crushed pills is rarer and likely to lead to bloodstream infections. Crushing pills effectively converts extended release and sustained release formulations to immediate release. The crystal form of methamphetamine is smoked.
Symptoms and Signs of Amphetamine Toxicity
The effects of use of amphetamines and its derivatives include increased alertness and concentration, euphoria, and paranoia. Palpitations, tremor, diaphoresis, and mydriasis may also occur.
Signs of toxicity include tachydysrhythmias, ranging from sinus tachycardia to ventricular tachycardia. There may be agitation and hyperactivity and seizures, with possible status epilepticus. Patients may have hyperthermia (body temperature greater than 40° C) and rhabdomyolysis. Patients with severe hyperthermia may present with a coagulopathy or multi-organ failure.
After periods of excessive use (binges), patients may develop a "washout" syndrome of intense fatigue and prolonged sleep that may last days. The washout period is thought to reflect the time needed to regenerate catecholamines. Some users experience a prolonged depression, during which they may attempt suicide and be driven to use again.
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In addition to direct toxicity, use of amphetamine or its derivatives may result in vascular hypertension. Use may precipitate hemorrhagic stroke through spikes in blood pressure and kidney failure caused by rhabdomyolysis. Necrotizing vasculitis that involves multiple organ systems can occur.
People who misuse amphetamines are prone to injury because the drug produces excitation and grandiosity followed by excess fatigue and sleepiness.
Use may be associated with sexual effects and risks. Amphetamines typically cause erectile dysfunction in men, but enhance sexual desire. Use is associated with unsafe sex practices, and users are at increased risk of sexually transmitted infections, including HIV infection.
Diagnosis of Amphetamine Toxicity
History and physical examination
ECG
Sometimes urine drug testing
The diagnosis of amphetamine toxicity is usually made based on history and physical examination, when patient reports ingestion of what they believe to be an amphetamine and demonstrate restlessness, agitation, tachycardia, or mydriasis. An ECG may show a tachydysrhythmia, such as sinus tachycardia or, in cases with rhabdomyolysis, peaked T waves or ventricular tachycardia from hyperkalemia.
The basic laboratory evaluation of a patient with suspected use of a xenobiotic is typically performed, including: complete metabolic profile; serum acetaminophen (paracetamol), salicylate, and ethanol concentrations; serum lactate and blood gas; urinalysis; and urine toxicology screen.
If there is no clear history of recent intentional ingestion of an amphetamine or there is a discordance between history and physical examination (eg, tachycardia and hyperthermia persist after taking a "downer"), a more extensive evaluation of altered mental status should be performed, including computed tomography of the brain, lumbar puncture, and laboratory tests to evaluate for infectious and metabolic etiologies. Here "downer" refers to a sedative-hypnotic medication taken by the patient, such as alcohol, a benzodiazepine, or an opioid. The discordance between clinical presentation and what the person believes they ingested may arise because the substance was adulterated with or misrepresented as a different substance, for example cocaine with fentanyl.
Amphetamine-induced paranoia or psychosis are not reliably distinguishable from primary psychiatric disorders. However, if symptoms and signs of autonomic nervous system dysregulation are present and/or psychosis resolves completely with cessation of amphetamine use, this suggests the etiology is amphetamine use than a primary psychiatric disorder.
Urine testing for amphetamine may be performed. The urine immunoassay tests for an epitope that amphetamine shares with its derivatives and many other substances, including ibuprofen, naproxen, and doxylamine. The lack of structural specificity of this immunoassay frequently leads to false-positive results or cross-reactions. However, methylphenidate (commonly used to treat attention deficit hyperactivity disorder) does not cross-react to produce a false positive in amphetamine testing.
Amphetamine testing is usually part of routine urine drug screening. In the United States, to support a drug-free workplace, the National Institute of Drug Abuse (NIDA) recommends standard testing for 5 drug groups (the "NIDA 5"): cannabinoids or marijuana, phencyclidine, opiates, amphetamines, and cocaine (1) (see drug testing).
Diagnosis reference
1. National Institutes of Health: National Institute on Drug Abuse. Drug Testing. Accessed February 18, 2025.
Treatment of Amphetamine Toxicity
For oral ingestion within 2 hours, oral activated charcoal
IV benzodiazepines as initial therapy
For severe agitation, ketamine or propofol
For cardiovascular effects unresponsive to benzodiazepines, IV nitrates or beta blockers
For hyperthermia, external cooling methods (e.g., ice bath, evaporative cooling)
Preventing absorption
Activated charcoal may be given if a patient ingested an amphetamine by mouth within the preceding 2 hours and can safely swallow thick liquids (ie, the consistency of honey). Based on pharmacological studies in poisoned animals, the recommended dose is 5 to 10 times that of the suspected toxin ingested. In clinical practice, one dose of 1 g/kg activated charcoal is given, up to a maximum of 50 g because the amount of toxin ingested is usually unknown. There is no recognized role for multiple doses of activated charcoal. In theory, activated charcoal limits absorption of xenobiotics that are in solid form. Activated charcoal will not limit the absorption of amphetamines that were inhaled, insufflated, or injected. Data demonstrating that activated charcoal reduces morbidity or mortality from amphetamine toxicity in humans are lacking; an animal study decreased toxicity (1). The clinician must weigh the potential benefits of activated charcoal against the risks of aspiration of charcoal and a resultant pneumonitis.
There is no routine role for gastric lavage. A medical toxicologist may recommend lavage for patients in whom preventing absorption is essential and activated charcoal is likely to be insufficient. There is usually no role for whole bowel irrigation, except for patients who have body packed the drug. Whole bowel irrigation and gastric lavage should be performed only if recommended by a toxicologist.
Enhancing excretion
There is no method to enhance the excretion of amphetamines.
Urine should NOT be acidified. Amphetamines are a weak base (pKa 10.3). Acidifying the urine could, in theory, increase the amount of amphetamine excreted. One study showed the fraction of amphetamine excreted in the urine increased from 10% to 70% after administration of oral ammonium chloride (2). However, acidifying the urine also decreases serum pH. Acidemia could increase the absorption of other drugs and will disrupt physiological processes.
Alkalinizing the urine will decrease the excretion of amphetamine and is also not recommended.
Mitigating toxicity
Benzodiazepines are the preferred initial treatment. They are given until agitation, seizures, tachycardia, and hypertension resolve. No particular benzodiazepine is superior to any other for this purpose. The clinician should chose based on local protocols, availability, current clinical context, and the guidance of a medical toxicologist. For intramuscular (IM) administration, midazolam is preferred. Midazolam has more reliable absorption IM than diazepam or lorazepam. If intravenous access is available, IV diazepam or lorazepam is preferred because they have a longer duration of action. Whatever the route of administration, higher doses may be required to treat sympathomimetic toxicity than clinicians typically use in other contexts, such as anxiolysis, treatment of muscle spasm, or for procedural sedation.
If benzodiazepines are ineffective, phenobarbital may be administered. Ketamine should be avoided because it has stimulant effects that could compound amphetamine toxicity. Propofol is a last resort because it its use may cause respiratory depression requiring ventilatory support such as mechanical ventilation. Poisoned patients should be intubated only after acid-base and electrolyte abnormalities are corrected unless the patient's airway needs to be controlled emergently.
Phenothiazines (eg, haloperidol) should not be used to treat agitation in patients with amphetamine toxicity. Phenothiazines mask central nervous system excitation through antihistamine and anticholinergic effects. They do not counteract the underlying hyperthermia or increased catecholamine release.
Cardiovascular effects that do not respond to benzodiazepines may require additional pharmacologic therapy, even if benzodiazepines have successfully treated other toxic symptoms. Persistent hypertension is treated with IV nitrates (nitroprusside or nitroglycerin); nicardipine or phentolamine may also be used but are not considered first line. Beta-blockers (eg, metoprolol 2 to 5 mg IV) may be used for ventricular dysrhythmias or persistent tachycardia. Beta blockers are a second-line treatment in amphetamine-induced hypertension because they do not treat sympathetic overdrive as directly as benzodiazepines. Central alpha agonists such as clonidine or dexmedetomidine are third-line agents for arrhythmias in the setting of amphetamine toxicity.
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Hyperthermia can be rapidly fatal and should be managed with external cooling. In the emergency department or intensive care unit, the most pragmatic approach is to submerge all but the patient's head in an ice bath or a "body bag" filled with ice. Submersion will usually decrease body temperatures from as high as 45° C to less than 40° C within 30 minutes. If submerging the patient in ice is not feasible, evaporative cooling (placing damp towels on the patient's unclothed body or misting the patient with tepid water, and using a fan for evaporation) should be used. If the patient is markedly agitated, pharmacologic paralysis may be necessary to prevent rhabdomyolysis. A nondepolarizing agent should be used to avoid worsening hyperkalemia. Paralyzed patients should be on continuous video electroencephalogram to evaluate for nonconvulsive status epilepticus. Paralysis silences the motor manifestations of a seizure but does not address the root causes of the seizure.
Treatment references
1. McKinney PE, Tomaszewski C, Phillips S, Brent J, Kulig K. Methamphetamine toxicity prevented by activated charcoal in a mouse model. Ann Emerg Med. 1994;24(2):220-223. doi:10.1016/s0196-0644(94)70133-4
2. Beckett AH, Rowland M. Urinary excretion kinetics of amphetamine in man. J Pharm Pharmacol. 1965;17(10):628-639. doi:10.1111/j.2042-7158.1965.tb07575.x
Chronic Use of Amphetamines
Complications
Continued use of amphetamines may result in paranoia and psychosis. With cessation of use, amphetamine-induced psychosis usually resolves. The florid psychosis fades within days to weeks. Confusion, memory loss, and delusions may persist. Users frequently have severe tooth decay affecting multiple teeth ("meth mouth") arising from decreased salivation, the direct action of acidic combustion products, bruxism, and poor oral hygiene.
Tolerance and dependence
Repeated use of amphetamines leads to tolerance and dependence. Users who develop tolerance can require doses hundreds of times higher than earlier doses to experience the same effects. With repeated use, tachycardia and increased alertness diminish. Hallucinations and delusions may persist or worsen..
Withdrawal
If people who chronically use amphetamines abruptly discontinue the drug, withdrawal symptoms typically start within 24 hours of the last use. They may experience dysphoria, fatigue, anxiety, irritability, insomnia or hypersomnia, or unpleasant dreams. These symptoms may unmask or exacerbate underlying depression, precipitating a major depressive episode. Severe symptoms may subside within a week, but some less severe symptoms, such as sleep disturbance, may last for weeks to months.
Key Points
Amphetamines are stimulants with euphoriant properties. There are many variants of amphetamines, which include illicit substances and therapeutic medications.
Toxicity is caused by excess catecholamine release and manifests as the sympathomimetic toxidrome (agitation, delirium, hypertension, seizures, and hyperthermia).
Ventricular dysrhythmias, status epilepticus, hyperthermia, and rhabdomyolysis are the most potentially life-threatening toxicities of amphetamines.
Diagnosis is based on history and physical examination and sometimes urine testing. Monitor for complications with an ECG.
For patients who took oral amphetamines within the previous 2 hours and who can safely tolerate liquids, treat with activated charcoal. Activated charcoal is not effective for other routes of use (eg, inhalation, injection).
Treat with benzodiazepines to control central nervous system excitement, hypertension, and tachycardia.
For severe agitation, consider phenobarbital and, as a last resort, propofol. Avoid ketamine. Propofol infusions may cause respiratory depression and necessitate mechanical ventilation, which itself is dangerous in the poisoned patient.
For cardiovascular effects unresponsive to benzodiazepines, treat with nitrates or beta blockers.
For hyperthermia unresponsive to benzodiazepines or exceeding 104, treat with external cooling methods (eg, ice bath or evaporative cooling).
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