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Summary Table

Domain	Details
Risk Factors	Young adults (18-35), males, history of substance use disorder, psychiatric comorbidities (ADHD, mood disorders), occupational stress, party/club culture, prior opioid or polysubstance use
Etiology	Exogenous sympathomimetic agents: cocaine (blocks monoamine reuptake), amphetamines/methamphetamine (promote monoamine release and block reuptake), MDMA, synthetic cathinones ("bath salts")
Patient Presentation	Intoxication: agitation, euphoria, chest pain, palpitations, paranoia. Withdrawal: hypersomnia, increased appetite, dysphoria, fatigue, psychomotor retardation
Classic Physical Exam	Intoxication: mydriasis, hypertension, tachycardia, hyperthermia, diaphoresis, psychomotor agitation. Withdrawal: no vital sign abnormalities, depressed affect, increased sleep
Key Diagnostic Results	Urine drug screen positive for cocaine metabolites (benzoylecgonine) or amphetamines; ECG showing sinus tachycardia or ischemic changes; elevated troponin if chest pain present
Management	Intoxication: benzodiazepines (first-line for agitation, seizures, hypertension, hyperthermia), IV fluids, cooling measures. Withdrawal: supportive care, no pharmacologic reversal agent. Avoid beta-blockers in cocaine toxicity
Keywords	"Found at a party," "chest pain in a young male," "dilated pupils with agitation," "crash" after binge, "paranoid and picking at skin," "formication," "excited delirium," "no antidote for withdrawal"

1. Pathophysiology

Stimulants exert their effects by augmenting catecholamine and serotonin signaling in the central and peripheral nervous systems. The two prototypical agents tested on exams are cocaine and amphetamines, and although they share a final common pathway of excessive monoamine activity, their mechanisms differ in an important and testable way.

Cocaine acts primarily as a reuptake inhibitor at the dopamine, norepinephrine, and serotonin transporters (DAT, NET, SERT). By blocking the presynaptic transporter, cocaine prevents clearance of these neurotransmitters from the synaptic cleft, leading to prolonged receptor stimulation. Cocaine also blocks voltage-gated sodium channels, which accounts for its local anesthetic properties and its propensity to cause cardiac arrhythmias (it essentially behaves like a Class I antiarrhythmic at toxic levels, widening QRS complexes). Additionally, cocaine promotes coronary artery vasospasm through alpha-1 adrenergic stimulation and enhances platelet aggregation, which together explain why a 25-year-old with no cardiac risk factors can present with an acute myocardial infarction.

Amphetamines (including methamphetamine) work through a different mechanism: they enter the presynaptic neuron via monoamine transporters and reverse the direction of the transporter, causing a flood of dopamine, norepinephrine, and serotonin into the synapse. They also inhibit monoamine oxidase (MAO) and vesicular monoamine transporter (VMAT), displacing stored neurotransmitters from vesicles into the cytoplasm and then into the synapse. The net result is a more sustained and prolonged sympathomimetic surge compared to cocaine, which is why amphetamine intoxication tends to last longer.

The euphoria and reward seen in intoxication are driven by dopamine release in the nucleus accumbens (the mesolimbic pathway). The psychosis and paranoia seen at higher doses result from excessive dopaminergic activity in the mesolimbic and mesocortical pathways. The peripheral sympathomimetic effects (tachycardia, hypertension, mydriasis, diaphoresis, hyperthermia) are mediated by excess norepinephrine acting on alpha and beta adrenergic receptors.

Withdrawal occurs because chronic stimulant use leads to downregulation of postsynaptic dopamine receptors and depletion of presynaptic dopamine stores. When the drug is abruptly discontinued, the brain enters a state of relative dopamine deficiency, producing the characteristic "crash" of profound fatigue, hypersomnia, increased appetite, and dysphoric mood. Unlike alcohol or benzodiazepine withdrawal, stimulant withdrawal is not medically dangerous and does not produce seizures or autonomic instability on its own. This distinction is a frequent test point.

2. Classification and Clinical Manifestation

Stimulant Intoxication

System	Cocaine	Amphetamines	MDMA (Ecstasy)
Onset/Duration	Rapid onset (seconds if smoked/IV); lasts 20-30 min	Onset within 30-60 min (oral); lasts 4-12 hours	Onset 30-60 min; lasts 3-6 hours
Cardiovascular	Tachycardia, hypertension, chest pain, MI, aortic dissection	Tachycardia, hypertension, palpitations	Tachycardia, hypertension
Neuropsychiatric	Euphoria, agitation, paranoia, seizures, psychosis, tactile hallucinations (formication)	Euphoria, hyperactivity, paranoia, stereotyped/repetitive behaviors, psychosis	Euphoria, empathy, emotional closeness, hallucinations
Autonomic	Mydriasis, diaphoresis, hyperthermia	Mydriasis, diaphoresis, hyperthermia, bruxism	Mydriasis, hyperthermia (often severe), bruxism, jaw clenching
Unique Features	Nasal septal perforation (chronic insufflation), sodium channel blockade (wide QRS), coronary vasospasm	"Meth mouth" (severe dental decay), skin excoriations from picking	Hyponatremia (SIADH + excessive water intake), serotonin syndrome-like picture
Life-Threatening	MI, arrhythmia, stroke, aortic dissection, seizures	Hyperthermia, rhabdomyolysis, intracranial hemorrhage, seizures	Severe hyperthermia, hyponatremia with cerebral edema, serotonin syndrome

Stimulant Withdrawal

Feature	Details
Timeline	Onset within hours to days after last use; peaks at 2-4 days; resolves within 1-2 weeks
Mood	Dysphoria, depression, anhedonia, irritability, anxiety
Sleep	Hypersomnia (the "crash"), vivid and unpleasant dreams
Appetite	Markedly increased
Motor	Psychomotor retardation or agitation
Cognition	Poor concentration, intense craving
Vital Signs	Normal (no autonomic instability, this is key)
Medical Danger	Not life-threatening (unlike alcohol, benzodiazepine, or opioid withdrawal)

Severity Spectrum of Intoxication

Severity	Presentation
Mild	Euphoria, talkativeness, increased energy, mild tachycardia, mydriasis
Moderate	Agitation, paranoia, diaphoresis, hypertension, chest pain, tremor
Severe	Psychosis, seizures, hyperthermia (>40C), rhabdomyolysis, cardiovascular collapse, "excited delirium"

3. Diagnostic Workup

Test	Purpose	Key Findings
Urine Drug Screen (UDS)	Best initial test for confirming substance exposure	Cocaine metabolite (benzoylecgonine): detectable 2-4 days. Amphetamines: detectable 1-3 days
ECG	Mandatory in any stimulant-related chest pain or tachycardia	Sinus tachycardia, ST changes (ischemia), wide QRS (cocaine sodium channel blockade), QTc prolongation
Troponin	Rule out myocardial infarction	Elevated if ischemia/infarction has occurred
Basic Metabolic Panel	Electrolyte abnormalities, renal function	Hyperkalemia (rhabdomyolysis), elevated creatinine, hyponatremia (MDMA)
Creatine Kinase (CK)	Evaluate for rhabdomyolysis	Markedly elevated (>5x upper limit of normal)
CT Head (non-contrast)	Focal neurologic deficit, altered mental status, seizure	Intracranial hemorrhage (hemorrhagic stroke), especially with amphetamine use
Chest X-ray	Chest pain, dyspnea	Pneumomediastinum (cocaine inhalation), pulmonary edema, aortic widening
CT Angiography of Aorta	Severe tearing chest pain radiating to back	Aortic dissection

The diagnostic approach to stimulant intoxication is largely clinical, based on the constellation of sympathomimetic signs (tachycardia, hypertension, mydriasis, agitation, diaphoresis) combined with the history. A urine drug screen serves as the best initial test to confirm exposure, but treatment should never be delayed while awaiting results. It is important to note that a positive UDS confirms recent exposure but does not confirm acute intoxication, since cocaine metabolites can persist for days.

An ECG is essential in any patient presenting with stimulant-related chest pain. In cocaine toxicity, look for ST-segment elevations (indicating ischemia from vasospasm or thrombosis) and QRS widening (indicating sodium channel blockade). If the ECG shows ischemic changes, troponin levels should be drawn serially.

CK levels should be obtained in any patient with prolonged agitation, hyperthermia, or seizures, as rhabdomyolysis is a common and potentially lethal complication. A CK greater than five times the upper limit of normal with myoglobinuria confirms the diagnosis.

For patients with focal neurologic deficits or persistent altered mental status, a non-contrast CT of the head should be obtained promptly to evaluate for hemorrhagic stroke, which is more common with amphetamine use due to severe hypertensive surges.

For withdrawal, the diagnosis is entirely clinical. There is no confirmatory test. The key diagnostic feature is the temporal relationship: a patient who was recently bingeing on stimulants now presents with the opposite symptom profile (hypersomnia, increased appetite, depressed mood, psychomotor slowing) with normal vital signs.

4. Management and Treatment

Intoxication Management

Clinical Problem	First-Line Treatment	Notes
Agitation / Psychosis	Benzodiazepines (lorazepam 2-4 mg IV/IM, or diazepam 5-10 mg IV)	Repeat every 5-10 min as needed. Avoid haloperidol as monotherapy (lowers seizure threshold, worsens hyperthermia)
Seizures	Benzodiazepines (lorazepam 4 mg IV, diazepam 10 mg IV)	If refractory: phenobarbital. Avoid phenytoin (ineffective for toxicologic seizures, worsens sodium channel blockade in cocaine)
Hypertension	Benzodiazepines first; if refractory, consider phentolamine, nicardipine, or nitroprusside	AVOID pure beta-blockers (see below)
Hyperthermia	Aggressive external cooling (ice packs, misting fans, cold IV fluids), benzodiazepines for agitation-driven thermogenesis	Antipyretics (acetaminophen) are ineffective because heat generation is muscular, not hypothalamic
Chest Pain / MI	Benzodiazepines, nitroglycerin, aspirin, calcium channel blockers. Cardiac catheterization if STEMI	AVOID beta-blockers in cocaine-associated MI
Wide QRS (cocaine)	Sodium bicarbonate (1-2 mEq/kg IV bolus)	Overcomes sodium channel blockade
Rhabdomyolysis	Aggressive IV normal saline	Target urine output 200-300 mL/hr
Excited Delirium	Benzodiazepines (high doses often required), physical cooling, IV fluids	Medical emergency with high mortality

Withdrawal Management

Intervention	Details
Supportive Care	Quiet environment, adequate nutrition, hydration, sleep
Depression/Suicidality	Monitor closely; consider inpatient psychiatric observation if actively suicidal
Pharmacotherapy	No FDA-approved medication for stimulant withdrawal or dependence
Long-term	Cognitive behavioral therapy (CBT), contingency management, motivational interviewing

Benzodiazepines are the cornerstone of acute stimulant intoxication management. They address agitation, seizures, hypertension, and tachycardia simultaneously by reducing central sympathetic outflow. The examiner will test whether you reach for benzodiazepines first rather than antipsychotics or antihypertensives.

The single most tested treatment pearl in stimulant toxicology is the avoidance of beta-blockers in cocaine intoxication. The rationale: cocaine stimulates both alpha and beta adrenergic receptors. If you block only the beta receptors (vasodilation, cardiac chronotropy), you leave alpha-mediated vasoconstriction unopposed, which can paradoxically worsen hypertension and precipitate coronary vasospasm. This is why labetalol (a combined alpha-beta blocker) remains controversial in this setting, and pure beta-blockers like propranolol and metoprolol are strictly contraindicated. If blood pressure remains elevated despite benzodiazepines, use phentolamine (a pure alpha-blocker), nicardipine, or nitroprusside.

For cocaine-associated myocardial infarction, the management mirrors standard ACS protocols with important modifications: administer benzodiazepines, aspirin, nitroglycerin, and consider calcium channel blockers. If the patient meets criteria for STEMI, proceed with percutaneous coronary intervention (PCI). Do not give beta-blockers. Fibrinolytics should be used with caution given the hypertensive state.

For cocaine-induced wide QRS complex or ventricular arrhythmias, administer sodium bicarbonate to counteract the sodium channel blockade. This is analogous to its use in tricyclic antidepressant toxicity.

Stimulant withdrawal management is entirely supportive. There is no reversal agent or taper protocol. The "crash" is self-limited and resolves within 1 to 2 weeks. The primary concern during withdrawal is suicidality secondary to profound depression, so psychiatric assessment is warranted. No medication has been proven effective for stimulant withdrawal or long-term maintenance therapy (unlike naltrexone for alcohol or methadone/buprenorphine for opioids). Behavioral interventions, particularly contingency management, have the strongest evidence for sustaining abstinence.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Anticholinergic toxidrome	Tachycardia, mydriasis, agitation, hyperthermia, altered mental status	Anticholinergic: dry skin, urinary retention, absent bowel sounds, flushed. Stimulant: diaphoresis (wet skin), active bowel sounds. "Blind as a bat, dry as a bone" = anticholinergic, not stimulant
Serotonin syndrome	Agitation, hyperthermia, tachycardia, diaphoresis, altered mental status	Serotonin syndrome: clonus (especially lower extremity), hyperreflexia, history of serotonergic drug use/interaction. Stimulants: no clonus, no hyperreflexia as a dominant feature
Neuroleptic malignant syndrome (NMS)	Hyperthermia, altered mental status, autonomic instability	NMS: "lead-pipe" rigidity, elevated CK, occurs after starting/increasing a dopamine antagonist. Stimulant: agitation without rigidity, occurs with dopamine agonism
Thyrotoxicosis / Thyroid storm	Tachycardia, diaphoresis, weight loss, agitation, tremor	Thyroid storm: goiter, exophthalmos, elevated free T4/T3, suppressed TSH. Stimulant: positive UDS, no thyroid findings
Pheochromocytoma	Episodic hypertension, tachycardia, diaphoresis, headache	Pheochromocytoma: episodic/paroxysmal pattern, elevated plasma metanephrines, adrenal mass. Stimulant: acute presentation with known substance use
Panic disorder	Tachycardia, diaphoresis, chest pain, sense of doom, hyperventilation	Panic disorder: normal pupils, normal temperature, negative UDS, no hypertension. Symptoms resolve spontaneously within 20-30 minutes
Primary psychotic disorder (schizophrenia)	Paranoia, hallucinations, disorganized behavior	Schizophrenia: auditory hallucinations predominate, chronic course, normal vital signs, negative UDS. Stimulant psychosis: tactile hallucinations (formication), acute onset with sympathomimetic signs, resolves with clearance of drug
Major depressive disorder (vs. stimulant withdrawal)	Depressed mood, hypersomnia, increased appetite, psychomotor retardation, anhedonia	MDD: insidious onset, duration >2 weeks, no temporal relationship to substance cessation. Stimulant withdrawal: acute onset after binge, self-limited (days), history of recent stimulant use

6. Traps and High-Yield Pearls

The most common way students lose points on stimulant questions is by confusing the toxidromes. The critical distinction between sympathomimetic and anticholinergic toxidromes rests on a single physical exam finding: skin moisture. Stimulant intoxication produces diaphoresis (wet skin) because sympathetic activation stimulates eccrine sweat glands. Anticholinergic toxicity produces dry skin because muscarinic blockade inhibits those same glands. When a vignette describes a tachycardic, mydriatic, agitated patient, immediately look for whether the skin is described as "flushed and dry" or "diaphoretic."

The second major trap is selecting a beta-blocker for cocaine-induced hypertension or chest pain. This is one of the most commonly tested "wrong answer" choices. Even labetalol, which has both alpha and beta blocking activity, is considered incorrect in the standard exam framework. The examiners are testing whether you understand the concept of "unopposed alpha stimulation." The correct answer for refractory hypertension in cocaine toxicity is benzodiazepines first, followed by phentolamine or a calcium channel blocker.

A third trap involves stimulant withdrawal. Students often assume that withdrawal from any substance is dangerous and requires pharmacologic intervention. The exam tests your understanding that stimulant withdrawal, while deeply unpleasant, is not medically life-threatening and has no validated pharmacologic treatment. The vignette will describe a patient with profound fatigue, increased sleep, increased appetite, and depressed mood after a cocaine or methamphetamine binge, and the correct management is supportive care. Do not select antidepressants for acute withdrawal management. The main concern warranting clinical attention is the risk of suicidal ideation during the depressive phase.

Finally, be alert to the MDMA-hyponatremia question. A young patient at a music festival or club who presents with seizures or altered mental status after taking ecstasy should prompt consideration of dilutional hyponatremia from SIADH combined with excessive free water intake, rather than (or in addition to) hyperthermia. The treatment is hypertonic saline if symptomatic, not just cooling.

The core competency being tested across all stimulant questions is your ability to recognize a sympathomimetic toxidrome by its physical exam findings, distinguish it from look-alike syndromes using one or two key discriminators, and select the correct pharmacologic intervention while avoiding the well-established contraindications.

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