Mechanism of action
Amphetamine is an indirect sympathomimetic agent that increases synaptic concentrations of dopamine, norepinephrine, and to a lesser extent serotonin through multiple mechanisms.
Primary mechanisms
- Enhanced neurotransmitter release: Amphetamine enters presynaptic terminals via dopamine and norepinephrine transporters (DAT and NET) and triggers reverse transport, causing massive release of stored catecholamines into the synaptic cleft
- Reuptake inhibition: Competitively blocks DAT and NET, preventing reuptake of dopamine and norepinephrine
- MAO inhibition: Weak inhibition of monoamine oxidase, reducing intracellular catecholamine metabolism
- VMAT2 interaction: Disrupts vesicular monoamine transporter function, redistributing catecholamines from synaptic vesicles to cytoplasm
The increased dopaminergic activity in the prefrontal cortex and striatum improves attention, executive function, and impulse control in ADHD. Enhanced noradrenergic transmission in the locus coeruleus and ascending reticular activating system promotes wakefulness and alertness in narcolepsy.
Amphetamine exists as dextroamphetamine (d-amphetamine) and levoamphetamine (l-amphetamine) enantiomers. Dextroamphetamine has greater CNS activity and preferentially affects dopamine, while levoamphetamine has more peripheral noradrenergic effects.
- Amphetamine is a Schedule II controlled substance with high abuse potential and risk of dependence.
- Mechanism: increases synaptic dopamine and norepinephrine by triggering reverse transport via DAT/NET and blocking reuptake.
- Absolute contraindication: concurrent MAOI use or within 14 days (hypertensive crisis risk).
- Urinary pH significantly affects elimination: acidic urine increases excretion, alkaline urine prolongs half-life.
- Black box warning: high potential for abuse; misuse may cause sudden death and serious cardiovascular events.
- Classic adverse effect with chronic high-dose use: amphetamine psychosis (paranoia, hallucinations).
- Pediatric concern: monitor growth parameters; amphetamine may suppress height and weight gain.
- Dextroamphetamine has greater CNS/dopaminergic effects; levoamphetamine has more peripheral noradrenergic effects.
Indications
FDA-approved indications
- Attention-deficit/hyperactivity disorder (ADHD): First-line pharmacotherapy in children aged 3 years and older, adolescents, and adults; improves attention span, reduces hyperactivity and impulsivity
- Narcolepsy: Treatment of excessive daytime sleepiness and cataplexy in patients aged 6 years and older
Off-label uses
- Treatment-resistant depression (adjunctive therapy)
- Binge eating disorder
- Cognitive enhancement in traumatic brain injury
Amphetamine is available in immediate-release and extended-release formulations. Mixed amphetamine salts contain a 3:1 ratio of dextroamphetamine to levoamphetamine. Dosing follows the product label and should be individualized based on therapeutic response and tolerability.
Pharmacokinetics
Absorption: Rapidly and completely absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations occur within 3 hours for immediate-release formulations and 7 hours for extended-release preparations.
Distribution: Widely distributed throughout the body including the CNS. Lipophilic structure allows easy blood-brain barrier penetration. Volume of distribution is approximately 3-5 L/kg. Moderate protein binding (15-40%).
Metabolism: Hepatic metabolism via CYP2D6 to active and inactive metabolites. Major pathways include aromatic hydroxylation, N-dealkylation, and deamination. The main metabolites are benzoic acid, hippuric acid, and norephedrine.
Excretion: Primarily renal excretion of unchanged drug and metabolites. Elimination half-life ranges from 9-14 hours, heavily dependent on urinary pH. Acidic urine (pH < 6) significantly increases excretion and shortens half-life to 7-8 hours. Alkaline urine (pH > 7.5) decreases excretion and prolongs half-life to 18-34 hours.
Special populations: Children may require weight-based dosing adjustments. Renal impairment prolongs elimination. CYP2D6 poor metabolizers may have altered drug response.
Adverse effects
Amphetamine produces dose-dependent adverse effects primarily related to excessive sympathomimetic stimulation.
Common adverse effects
- Cardiovascular: Tachycardia, palpitations, hypertension, increased heart rate and blood pressure (monitor in all patients)
- CNS: Insomnia, restlessness, anxiety, irritability, dizziness, headache, tremor
- Gastrointestinal: Decreased appetite, weight loss, dry mouth, nausea, abdominal pain, constipation
- Psychiatric: Mood changes, agitation, nervousness
- Other: Excessive sweating, mydriasis, bruxism
Serious adverse effects
- Cardiovascular events: Myocardial infarction, stroke, sudden cardiac death (rare but reported, especially in patients with structural cardiac abnormalities)
- Psychiatric: Amphetamine psychosis (paranoia, hallucinations, delusions) with chronic use or high doses; exacerbation of pre-existing psychotic disorders, mania in bipolar disorder
- Growth suppression: Slowing of growth rate and weight gain in pediatric patients during prolonged use (monitor height and weight)
- Peripheral vasculopathy: Raynaud phenomenon, digital ulceration (rare)
- Serotonin syndrome: When combined with other serotonergic agents
- Hyperthermia: Potentially life-threatening, especially with overdose or in hot environments
- Seizures: Lowered seizure threshold
Withdrawal syndrome
Abrupt discontinuation after chronic use produces fatigue, depression, hypersomnia, and increased appetite. Gradual dose reduction is recommended.
Black box warning
Amphetamine has high potential for abuse and dependence (Schedule II controlled substance). Prolonged use may lead to psychological and physical dependence. Misuse may cause sudden death and serious cardiovascular adverse events.
Contraindications and warnings
Absolute contraindications
- Hypersensitivity to amphetamine or any formulation component
- Advanced arteriosclerosis or symptomatic cardiovascular disease
- Moderate to severe hypertension
- Hyperthyroidism or thyrotoxicosis
- Glaucoma (angle-closure type)
- Agitated states or history of drug abuse
- Concurrent use or within 14 days of MAOI therapy (risk of hypertensive crisis)
Warnings and precautions
Cardiovascular: Perform cardiovascular assessment before initiation. Avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac conditions. Monitor blood pressure and heart rate at baseline and periodically during treatment.
Psychiatric: Screen for personal or family history of bipolar disorder, psychosis, or suicide risk before initiating treatment. May induce manic or mixed episodes in patients with bipolar disorder. Can cause treatment-emergent psychotic or manic symptoms even in patients without prior psychiatric history.
Seizures: Use with caution in patients with history of seizures; may lower seizure threshold.
Growth monitoring: Monitor height and weight in pediatric patients; consider drug holidays to allow catch-up growth if significant suppression occurs.
Pregnancy: Pregnancy category C. Amphetamine crosses the placenta. Neonates born to mothers taking amphetamine may experience withdrawal symptoms including agitation and dysphoria. Use only if potential benefit justifies fetal risk. Infants exposed in utero may have increased risk of premature birth and low birth weight.
Lactation: Excreted in breast milk. Use caution or consider alternative feeding methods.
Elderly: Increased sensitivity to adverse effects, particularly cardiovascular effects.
Phenylketonuria: Some formulations contain phenylalanine.
Drug interactions
Major interactions
MAO inhibitors: Contraindicated combination. MAOIs (phenelzine, tranylcypromine, selegiline at higher doses) prevent catecholamine metabolism, leading to hypertensive crisis, hyperpyrexia, seizures, and death. Allow 14-day washout period between MAOI discontinuation and amphetamine initiation.
Serotonergic agents: SSRIs, SNRIs, triptans, linezolid, St. John's wort, and tramadol increase serotonin syndrome risk (agitation, hyperthermia, hyperreflexia, clonus, autonomic instability).
Urinary acidifying agents: Ammonium chloride, ascorbic acid, and acidifying foods increase renal excretion and decrease amphetamine efficacy. Urinary alkalinizing agents (sodium bicarbonate, acetazolamide, some antacids) decrease excretion and prolong effects, increasing toxicity risk.
Antihypertensives: Amphetamine may antagonize antihypertensive effects of guanethidine, methyldopa, and reserpine.
Tricyclic antidepressants: Enhanced cardiovascular effects; increased risk of hypertension and arrhythmias due to increased synaptic norepinephrine.
Moderate interactions
- CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine): May increase amphetamine concentrations
- Proton pump inhibitors and H2 blockers: May alter absorption of extended-release formulations
- Anticonvulsants: Amphetamine may decrease seizure threshold, potentially requiring anticonvulsant dose adjustment
- Haloperidol and chlorpromazine: Antipsychotics may block dopaminergic effects of amphetamine
- Ethanol: Concurrent use not recommended; unpredictable cardiovascular effects
Pharmacodynamic considerations: Combining amphetamine with other sympathomimetics (pseudoephedrine, phenylephrine, cocaine) produces additive cardiovascular stimulation and increased adverse effect risk.
Clinical pearls
- Tolerance development: Tachyphylaxis to anorectic and euphoric effects occurs with chronic use, but therapeutic effects in ADHD typically remain stable at appropriate doses
- Drug holidays: Some clinicians recommend periodic drug-free periods (weekends, summer breaks) in pediatric ADHD patients to allow catch-up growth and reassess need for continued therapy
- Urinary pH matters: Emphasize dietary counseling; high-protein diets acidify urine and reduce drug efficacy, while vegetarian diets may alkalize urine and prolong effects
- Sudden death risk: Pre-treatment ECG is not routinely required in healthy children but should be considered with personal or family history of cardiac disease, syncope, or arrhythmias
- Misuse patterns: Crushing and insufflation or intravenous injection of immediate-release formulations is common in substance abuse; extended-release formulations with abuse-deterrent properties were developed to mitigate this
- Differential diagnosis: In patients presenting with sympathomimetic toxidrome, consider amphetamine intoxication along with cocaine, MDMA, synthetic cathinones, and caffeine overdose
- Neurotoxicity concerns: Chronic high-dose methamphetamine (not therapeutic amphetamine) causes dopaminergic neurotoxicity; standard therapeutic doses of amphetamine for ADHD have not demonstrated neurotoxic effects
- Athletic performance: Banned by most athletic organizations; some students misuse amphetamine as a "study drug" or cognitive enhancer
- Pregnancy screening: Consider pregnancy testing in women of childbearing age before initiating therapy given teratogenic concerns and neonatal withdrawal risk
AMPHETAMINE adverse effects: Anxiety, Mydriasis, Psychosis, Hypertension, Euphoria, Tachycardia, Anorexia, Mydriasis, Insomnia, Neurotoxicity (high doses), Elevated BP
Practice questions
1. A 9-year-old boy with ADHD is started on amphetamine therapy. Two weeks later, his mother calls reporting that he is having difficulty falling asleep and has lost 3 pounds. His teacher reports significant improvement in classroom behavior and attention. Vital signs show BP 118/76 mmHg and HR 96/min. Which of the following is the most appropriate next step in management?
2. A 34-year-old woman with depression on tranylcypromine presents to the emergency department with severe headache, diaphoresis, and confusion 3 hours after taking her friend's ADHD medication. Vital signs show BP 210/120 mmHg, HR 110/min, and temperature 38.9°C (102°F). Pupils are dilated bilaterally. Which of the following drug combinations best explains this presentation?
3. A 28-year-old graduate student is brought to the emergency department by friends with paranoid delusions, visual hallucinations, and aggressive behavior. He has been awake for 72 hours preparing for exams. Vital signs show BP 165/95 mmHg, HR 115/min, temperature 37.8°C (100°F). He is diaphoretic with dilated pupils and picking at his skin. Urine drug screen is positive for amphetamines. Which of the following best explains the psychiatric symptoms?
Frequently asked questions
How does amphetamine work?
Amphetamine increases synaptic concentrations of dopamine and norepinephrine by entering presynaptic terminals and triggering reverse transport through dopamine and norepinephrine transporters, causing massive neurotransmitter release. It also blocks reuptake of these catecholamines, prolonging their action in the synapse. The enhanced dopaminergic activity in the prefrontal cortex improves attention and executive function in ADHD, while increased noradrenergic transmission promotes wakefulness in narcolepsy.
What are the side effects of amphetamine?
Common side effects include decreased appetite, weight loss, insomnia, increased heart rate, elevated blood pressure, anxiety, restlessness, and dry mouth. Serious adverse effects include cardiovascular events such as myocardial infarction and stroke (rare), amphetamine psychosis with chronic use (paranoia and hallucinations), growth suppression in children, and serotonin syndrome when combined with other serotonergic drugs. Amphetamine has high abuse potential and can cause psychological and physical dependence.
Is amphetamine a controlled substance?
Yes, amphetamine is a Schedule II controlled substance under the Controlled Substances Act, indicating it has accepted medical uses but high potential for abuse and severe psychological or physical dependence. Prescriptions cannot be refilled and require a new written or electronic prescription for each dispensing. This classification reflects the significant risk of misuse, diversion, and addiction associated with amphetamine products.
Can you take amphetamine with antidepressants?
Amphetamine is absolutely contraindicated with MAO inhibitors due to risk of hypertensive crisis; a 14-day washout is required after stopping MAOIs. Concurrent use with SSRIs or SNRIs increases serotonin syndrome risk and requires careful monitoring for symptoms like agitation, hyperthermia, and hyperreflexia. Tricyclic antidepressants combined with amphetamine enhance cardiovascular effects and increase risk of hypertension and arrhythmias. Any combination with antidepressants should be carefully monitored by a healthcare provider.
Amphetamine vs methylphenidate — what is the difference?
Both are first-line CNS stimulants for ADHD, but their mechanisms differ. Amphetamine triggers active release of dopamine and norepinephrine via reverse transport and blocks reuptake, while methylphenidate primarily blocks reuptake without triggering release. Amphetamine generally has greater potency and longer duration of action. Methylphenidate may have slightly lower abuse potential and fewer peripheral sympathomimetic effects. Both are Schedule II controlled substances with similar efficacy in ADHD, and choice depends on individual response, tolerability, and duration of action needed.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: N06BA01
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.