Caffeine is the most widely used psychoactive substance. Besides its well-known presence in coffee, tea, colas, and chocolate, it is available in many over-the-counter and prescription oral medications and as injectable caffeine sodium benzoate (occasionally used for neonatal apnea). Caffeine is widely used as an appetite suppressant, a co-analgesic, a diuretic, and a sleep suppressant. Pure caffeine sold on the internet has been associated with accidental death due to overdose. Botanical forms of caffeine, including yerba mate, guarana (Paullinia cupana), kola nut (Cola nitida), and green tea extract, are common constituents of “thermogenic” dietary supplements touted for weight loss and athletic enhancement. Caffeine is occasionally combined in tablets with other stimulants, such as MDMA (methylenedioxymethamphetamine). Although caffeine has a wide therapeutic index and rarely causes serious toxicity, there are many documented cases of accidental, suicidal, and iatrogenic intoxication, some resulting in death.

1. Caffeine is a trimethylxanthine that is closely related to theophylline. It acts primarily through nonselective inhibition of adenosine receptors. In addition, with overdose there is considerable beta₁- and beta₂-adrenergic stimulation secondary to release of endogenous catecholamines. In addition to cardiovascular effects, sympathetic neural stimulation results in increased levels of lactate, glucose and ketones.
2. Consumption of caffeinated alcoholic beverages can decrease subjective perception of alcohol intoxication without affecting objective markers of intoxication such as motor control, and may increase risky sexual behavior and injury.
3. Pharmacokinetics. Caffeine is rapidly and completely absorbed orally, with a volume of distribution of 0.7-0.8 L/kg. Its elimination half-life is approximately 4-6 hours but can range from 3 hours in healthy smokers to 10 hours in nonsmokers; after overdose, the half-life may be as long as 15 hours. In infants younger than 2-3 months old, metabolism is extremely slow, and the half-life may exceed 24 hours. Caffeine is metabolized in the liver primarily by cytochrome P450 1A2 and is subject to several potential drug interactions, including inhibition by oral contraceptives, cimetidine, norfloxacin, and alcohol. Tobacco (and marijuana) smoking accelerates caffeine metabolism.

The reported lethal oral dose is 10 g (150-200 mg/kg), although one case report documents survival after a 24-g ingestion. In children, ingestion of 35 mg/kg may lead to moderate toxicity. Coffee contains 50-200 mg (tea, 40-100 mg) of caffeine per cup depending on how it is brewed. NoDoz and other sleep suppressants usually contain about 200 mg per tablet. “Thermogenic” dietary supplements, which are sold as energy beverages, bars, capsules, tablets, or liquid drops, contain the equivalent of 40-200 mg of caffeine per serving as either concentrated plant extracts or synthetic caffeine. For information about caffeine content of common products, see https://www.caffeineinformer.com/the-caffeine-database.

1. The earliest symptoms of acute caffeine poisoning are usually anorexia, tremor, and restlessness, followed by nausea, vomiting, tachycardia, and agitation. With serious intoxication, delirium, seizures, supraventricular and ventricular tachyarrhythmias, hypokalemia, and hyperglycemia may occur. Hypotension is caused by excessive beta₂-mediated vasodilation and is characterized by a low diastolic pressure and a wide pulse pressure. Ingestion of caffeine-containing diet aids has been associated with sudden death in people with bulimia or laxative abuse, most likely owing to aggravation of hypokalemia. Caffeine poisoning occasionally causes rhabdomyolysis and acute renal failure. Coronary vasospasm has also been described. Concomitant administration of caffeine with MDMA aggravated tachycardia and hyperthermia in animals.
2. Chronic high-dose caffeine intake can lead to “caffeinism” (nervousness, irritability, anxiety, tremulousness, muscle twitching, insomnia, palpitations, and hyperreflexia).

Is suggested by the history of caffeine exposure or the constellation of nausea, vomiting, tremor, tachycardia, seizures, and hypokalemia (also consider theophylline).

1. Specific levels. Serum caffeine levels are not routinely available in hospital laboratories but can be determined at reference toxicology laboratories. Some pediatric hospitals may offer caffeine testing for monitoring therapeutic use in neonates. Coffee drinkers have caffeine levels of 1-10 mg/L, and levels exceeding 80 mg/L have been associated with death. The level associated with a high likelihood of seizures is unknown. Serum caffeine and lactate levels are highly correlated after caffeine overdose, and lactate has been proposed as a surrogate when caffeine levels are not available.
2. Other useful laboratory studies include electrolytes, lactate, glucose, urinary ketones, creatine kinase, BUN, creatinine, cardiac troponin, ECG, and telemetry monitoring.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat seizures and hypotension if they occur. Extreme anxiety or agitation may respond to benzodiazepines such as IV lorazepam.
   3. Hypokalemia usually resolves without treatment, but in severe cases it may be necessary (see Potassium) as it can contribute to life-threatening arrhythmias.
   4. Monitor ECG and vital signs for at least 6 hours after ingestion.
2. Specific drugs and antidotes
   1. Beta blockers effectively reverse cardiotoxic and hypotensive effects mediated by excessive beta-adrenergic stimulation. Treat tachyarrhythmias and hypotension with IV propranolol, 0.01-0.02 mg/kg, or esmolol, 0.025-0.1 mg/kg/min, beginning with low doses and titrating to effect. Because of its short half-life and cardioselectivity, esmolol is preferred for tachyarrhythmias in normotensive patients. Adenosine may not be effective in reversal of supraventricular tachycardias, because of adenosine receptor antagonism.
   2. If vasopressor drugs are required, vasopressin (p 595) or phenylephrine is recommended to avoid the potassium-lowering effects of catecholamines.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination. Repeat-dose activated charcoal may enhance caffeine elimination. Seriously intoxicated patients (with multiple seizures, significant tachyarrhythmias, or intractable hypotension) may require hemodialysis.