Cocaine, Other Psychostimulants, and Hallucinogens¶

Chapter 468 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 468

Key Clinical Points¶

Cocaine binds to the dopamine (DA) transporter, blocking reuptake and increasing synaptic levels of DA, norepinephrine (NE), and serotonin (5HT).
Methamphetamine stimulates release and partially blocks reuptake of catecholamines while inhibiting monoamine oxidase.
MDMA binds to serotonin transporters, increasing release of 5HT, NE, and DA; high doses can cause loss of serotonin-containing nerve endings.
Cocaethylene (metabolite of cocaine + alcohol) has additive effects on the cardiovascular system, intensifying pathophysiologic consequences.
Adulterants like Levamisole can cause agranulocytosis, leukoencephalopathy, and cutaneous vasculitis (skin necrosis); Xylazine causes a range of symptoms including dry mouth, drowsiness, hypertension/tachycardia → hypotension/bradycardia, hyperglycemia, hypothermia, coma, respiratory depression, and dysrhythmia.
Acute cocaine intoxication is a medical emergency; use benzodiazepines (e.g., diazepam 10 mg IV, then 5–10 mg every 3–5 hours) for agitation.
Avoid succinylcholine for intubation in cocaine patients; use rocuronium (1 mg/kg IV).
For severe hypertension in cocaine cases, use phentolamine, nitroglycerin, or nitroprusside; avoid nonselective beta-blockers due to risk of unoppressed alpha-adrenergic stimulation.
DSM-5 defines stimulant use disorder as ≥ 2 of 11 criteria over a 12-month period; the withdrawal criterion does not apply to hallucinogens.
Synthetic cathinones (bath salts) are chemically similar to khât and are often more potent/dangerous than natural products.
MDMA has an FDA breakthrough therapy designation for PTSD but remains a Schedule I drug.
Polydrug use, such as 'speedballs' (cocaine + opioids), significantly increases risk of infection (HIV).

DEFINITION & OVERVIEW¶

• Overview: Interaction between pharmacology, individual personality/expectations, and environmental context. • Polydrug Use: Common; often used to enhance effects (e.g., cocaine + nicotine or cocaine + heroin). • High-Risk Combinations: Intravenous (IV) heroin and cocaine are especially dangerous and frequent in emergency departments.

• Classification of Psychostimulants: ◦ Cocaine ◦ Methamphetamine ◦ MDMA ◦ Cathinones ◦ Prescription Stimulants: methylphenidate, dextroamphetamine, and amphetamine.

• Pharmacology: ◦ Mechanism: Cocaine binds to the dopamine (DA) transporter → blocks reuptake → increases synaptic levels of DA, norepinephrine (NE), and serotonin (5HT) in both CNS and PNS. ◦ Long-term effects: Induces long-term changes in the brain; animal studies show adaptations in neurons that release the excitatory neurotransmitter glutamate.

EPIDEMIOLOGY¶

• Cocaine: ◦ 2023: ~5 million people (1.8% of population) were past-year consumers. ◦ 470,000 first-time users; 1.3 million with cocaine use disorder. ◦ Overdose deaths involving cocaine more than quintupled from 2011 to 2022 (1.5 → 8.2 per 100,000). ◦ Cocaine + Opioids: Rate in 2021 (5.9) was 7.4 times the rate in 2011 (0.8), driven by synthetic opioids like fentanyl.

• Methamphetamine: ◦ 2023: 2.6 million users; 1.8 million with methamphetamine use disorder. ◦ Overdose deaths from psychostimulants (primarily meth) rose from 0.7 in 2011 to 10.4 in 2022.

• MDMA: ◦ 2023: 0.8% of population used MDM; 507,000 first-time users. ◦ Predominantly used by men aged 18–25; usage often begins at age 21.

• Hallucinogens: ◦ 2023: 8.8 million (3.1%) reported past-year use; 1.5 million first-time users. ◦ Includes MDMA, LSD, PCP, peyote, mescaline, psilocybin mushrooms, ketamine, N,N-dimethyltryptamine (DMT), Alpha-Methyltryptamine (AMT/"Foxy"), and S. divinorum.

• Prescription Stimulant Misuse: ◦ 2023: 3.9 million (1.4%) reported misuse. ◦ High rates of concurrent use with cocaine and methamphetamine.

ETIOLOGY & PATHOPHYISIOLOGY¶

• Mechanism of Action: ◦ Cocaine binds to DA transporter → blocks reuptake → increases synaptic monoamines (DA, NE, 5HT) in CNS and PNS.

• Pathogenesis Cascade: ◦ Chronic use → immune system dysfunction → increased vulnerability to infections (e.g., HIV). ◦ "Speedball" (cocaine + opiates) → frequent needle sharing → high risk of HIV transmission.

CLINICAL FEATURES¶

• General Psychostimulant Effects: ◦ CNS: Euphoria, increased energy, reduced fatigue/sleep need, decreased appetite, heightened alertness, increased confidence, increased libido. ◦ Peripheral: Tremor, diaphoresis, hypertonia, tachypnea, hyperreflexia, hyperthermia. ◦ Biphasic Nature: ◦ α-Adrenergically mediated cardiovascular effects: → Low doses: Increased vagal tone and decreased heart rate. → High doses: Increased heart rate and blood pressure. ◦ Behavioral: Restlessness, irritability, insomnia; at higher doses, suspiciousness, repetitive stereotyped behaviors, and bruxism.

• Chronic Effects: ◦ Endocrine: Impotence, gynecomastia, menstrual dysfunction, hyperprolactinemia.

• Acute Intoxication: ◦ Sympathetic overactivity: Psychomotor agitation, hypertension, tachycardia, headache, mydriasis. ◦ Severe risks: Convulsions, cerebral hemorrhage/infarction, cardiac arrhythmias/ischemia, respiratory failure, rhabdomyolysis. ◦ Inhaled Crack Cocaine: Airway burns, bronchospasm, pulmonary disease.

• Withdrawal: ◦ Symptoms: Hypersomnia, increased appetite, depressed mood. ◦ Mechanism: Driven by conditioned craving (cues like associates, paraphernalia, locations) rather than just physiological withdrawal.

• Adulterant Effects: ◦ Fentanyl-related compounds → fatal overdose. ◦ Levamisole → agranulocytosis, leukoencephalopathy, cutaneous vasculitis, skin necrosis. ◦ Xylazine → dry mouth, drowsiness, hypertension/tachycardia → hypotension/bradycardia, hyperglycemia, hypothermia, coma, respiratory depression, dysrhythmia.

• Table 468-1 (Complications of Psychostimulant Use): ◦ Cardiovascular: Arterial vasoconstriction, thrombosis, tachycardia, hypertension, increased myocardial oxygen demand, increased vascular shearing forces, coronary vasoconstriction, cardiac ischemia, LV dysfunction/heart failure (high concentrations), arrhythmias, aortic dissection/rupture; Chronic → accelerated atherogenesis, LVH, dilated cardiomyopathy. ◦ Pulmonary: Angioedema (inhaled), pharyngeal burns (inhaled), pneumothorax, pneumomediastinum, pneumopericardium, reversible airway disease exacerbations, bronchospasm, "crack lung" (shortness of breath). ◦ Renal: Metabolic acidosis, renal infarction, rhabdomyolysis. ◦ Other: Diaphoresis, irritability, insomnia, bruxism, stereotypy, splenic infarction, acute angle-closure glaucoma, vasospasm of retinal vessels, mydriasis, madarosis, abruptio placentae.

DIFFERENTIAL DIAGNOSIS¶

• Acute Intoxication: ◦ Pheochromocytoma ◦ Hyperthyroidism ◦ Panic disorder

• Withdrawal: ◦ Depression ◦ Anxiety disorders ◦ Other substance withdrawal syndromes

• Hallucinogen Use Disorder: ◦ Other psychotic disorders ◦ Mood disorders

DIAGNOSTIC APPROACH¶

Acute Toxicity Assessment ◦ Assess ABC (Airway, Breathing, Circulation). ◦ Rule out life-threatening conditions (e.g., hypoxemia, hypoglycemia) if psychomotor agitation is present.
Formal Diagnosis ◦ Stimulant Use Disorder: Identify ≥ 2 of 11 DSM-5 criteria over a 12-month period. ◦ Hallucinogen Use Disorder: Identify ≥ 2 of the first 10 DSM-5 criteria (withdrawal criterion not applicable). ◦ Clinical Correlation: Recognize "stimulant dependence syndrome" and "stimulant withdrawal state."

MANAGEMENT & TREATMENT¶

Immediate Stabilization ◦ Assess ABC (Airway, Breathing, Circulation). ◦ Intubation Preparation: → Avoid succinylcholine. → Use rocuronium (1 mg/kg IV) or other non-depolarizing agents.
Agitation Management ◦ Administer benzodiazepines (e.g., diazepam 10 mg IV, then 5–10 mg every 3–5 hours until controlled).
Cardiovascular Management ◦ Severe/Symptomatic Hypertension: Treat with phentolamine, nitroglycerin, or nitroprusside. ◦ Beta-blocker Caution: Avoid nonselective beta-blockers due to risk of unoppressed alpha-adrenergic stimulation → coronary vasoconstriction.
Hyperthermia Management ◦ Address hyperthermia as a clinical complication (as noted in Table 468-1).
Long-term Treatment ◦ Behavioral therapies: CBT, CRA, contingency management (CM), motivational enhancement therapy (MET). ◦ Contingency Management: Highly effective for psychostimulant use disorder.

PROGNOSIS & COMPLICATIONS¶

• Overdose Statistics: ◦ Significant increase in cocaine-related deaths, especially when combined with synthetic opioids.

• Treatment Gap: ◦ Only about one-third of adults with methamphetamine use disorder receive treatment.

SPECIAL CONSIDERATIONS¶

• Polydrug Use: ◦ "Speedball" (cocaine + opioids) → high risk for HIV and other infections.

• Emerging Drugs: ◦ Synthetic cathinones (bath salts): Chemically similar to khât; often stronger/more dangerous. ◦ Xylazine: Common in cocaine/methamphetamine; causes severe systemic effects including respiratory depression.

• Substance Use and Mental Health: ◦ High rates of co-occurring mental illness in methamphetamine users.

KEY PEARLS & CLINICAL TRAPS¶

• Cocaine Pharmacology: Blocks DA reuptake → increases DA, NE, 5HT. ◦ Cocaethylene: Additive cardiovascular effects; intensifies pathophysiology. ◦ Levamisole: Watch for agranulocytosis and skin necrosis. ◦ Xylazine: Watch for hypotension/bradycardia and respiratory depression. ◦ Intubation: Succinylcholine is contraindicated; use rocuronium (1 mg/kg IV). ◦ Hypertension: Avoid nonselective beta-blockers due to risk of coronary vasoconstriction. ◦ MDMA: Breakthrough therapy for PTSD, but remains a Schedule I drug. ◦ Contingency Management: Highly effective evidence-based treatment for psychostimulant use disorder.

Reference Tables¶

TABLE 468-1 Complications of Psychostimulant Use Cardiovascular¶

Harrison's 22e, p.3694

Cardiovascular	Acute • Arterial vasoconstriction • Thrombosis • Tachycardia • Hypertension • Increased myocardial oxygen demand • Increased vascular shearing forces • Coronary vasoconstriction • Cardiac ischemia • Left ventricular dysfunction/heart failure (high blood concentrations) • Supraventricular and ventricular dysrhythmias • Aortic dissection/rupture Chronic • Accelerated atherogenesis • Left ventricular hypertrophy • Dilated cardiomyopathy
Pulmonary	• Angioedema (inhaled) • Pharyngeal burns (inhaled) • Pneumothorax • Pneumomediastinum • Pneumopericardium • Reversible airway disease exacerbations • Bronchospasm • Shortness of breath (“crack lung”) • Tachypnea • Pulmonary infarction
Renal	• Metabolic acidosis • Renal infarction • Rhabdomyolysis
Other	• Diaphoresis • Irritability • Insomnia • Bruxism • Stereotypy • Splenic infarction • Acute angle-closure glaucoma • Vasospasm of the retinal vessels (unilateral or bilateral vision loss) • Mydriasis • Madarosis • Abruptio placentae