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Caffeine Toxicity

  • Author: David Yew, MD; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Mar 31, 2014
 

Practice Essentials

Caffeine (1,3,7-trimethylxanthine) (see the image below) is the most widely consumed stimulant drug in the world. It is present in a variety of forms: medications, coffee, tea, soft drinks, and chocolate. Because caffeine overdoses, intentional or unintentional, are relatively common in the United States, physicians and other medical personnel must be aware of caffeine toxicity to recognize and treat it appropriately.

Chemical structure of caffeine. Chemical structure of caffeine.

Signs and symptoms

When acute caffeine ingestion is suspected, the history should address the following:

  • Use of prescription medications or over-the-counter (OTC) drugs
  • Use of illicit drugs
  • Recent caffeine ingestion recent behavior compatible with such ingestion

When ingested in excessive amounts for extended periods, caffeine produces a specific toxidrome (caffeinism), which consists primarily of the following:

  • Central nervous system (CNS) features – Headache, lightheadedness, anxiety, agitation, tremulousness, perioral and extremity tingling, confusion, psychosis, seizures
  • Cardiovascular features – Palpitations or racing heart rate, chest pain
  • Gastrointestinal (GI) features – Nausea and vomiting, abdominal pain, diarrhea, bowel incontinence, anorexia

CNS findings on physical examination include the following:

  • Anxiety, agitation
  • Tremors
  • Seizures
  • Altered mental status
  • Head, eyes, ears, nose, and throat findings
  • Pupils that are dilated but reactive to light

The thyroid should be examined because thyrotoxicosis may mimic caffeine toxicity.

Cardiovascular findings on physical examination include the following:

  • Widened pulse pressure
  • Sinus tachycardia, dysrhythmias
  • Hypotension
  • Tachypnea

GI findings on physical examination include the following:

  • Vomiting
  • Abdominal cramping
  • Hyperactive bowel sounds

See Presentation for more detail.

Diagnosis

In hemodynamically stable patients with mild symptoms and a clear history of caffeine ingestion, no laboratory studies are indicated. Laboratory studies are indicated in patients with moderate-to-severe symptoms of caffeine toxicity. The following studies may be helpful:

  • Complete blood count (CBC)
  • Serum electrolyte, glucose, blood urea nitrogen (BUN), and creatinine concentrations
  • Routine screening for other potentially treatable toxins
  • Total creatine kinase (CK) concentrations
  • Dipstick urinalysis
  • Rapid urine drug screen
  • Serum ethanol concentrations and osmolality (in cases of unknown ingestion or suspected coingestion)
  • Serum pregnancy test
  • Thyroid studies
  • Arterial blood gas analysis

Serum caffeine concentration determinations do not influence management.

In hemodynamically stable patients with only mild symptoms, no diagnostic imaging is required. The following studies may be considered in particular circumstances:

  • Chest radiograph – In patients with chest pain, fever, altered mental status, or respiratory complaints
  • Unenhanced computed tomography (CT) of the head – In patients with seizures or altered mental status despite initial resuscitation

Patients with chest pain, palpitations, tachycardia, or an irregular heart rhythm should be evaluated with electrocardiography (ECG) and telemetry monitoring.

See Workup for more detail.

Management

Prehospital care is primarily supportive, and most cases resolve. Emergency management of more severe cases includes the following:

  • ABCs ( A irway, B reathing, C irculation)
  • Management of hypotension
  • Correction of dysrhythmias
  • Management of seizures (with benzodiazepines or barbiturates)
  • Correction of metabolic disturbances (hypokalemia, rhabdomyolysis, hyperglycemia, metabolic acidosis)
  • Treatment of prolonged vomiting
  • Decontamination with activated charcoal, sorbitol, or both
  • In rare severe cases, hemoperfusion or hemodialysis

Consultations may include a regional poison control center, a medical toxicologist, or a psychiatrist (once the patient is medically stable). Medically unstable patients are admitted for the appropriate level of care, depending on the clinical presentation.

See Treatment and Medication for more detail.

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Background

Caffeine (1,3,7-trimethylxanthine; see the image below) is the most widely consumed stimulant drug in the world. It is present in a variety of forms: medications, coffee, tea, soft drinks, and chocolate. About 80% of adults in the United States consume caffeine in the form of coffee or tea on a daily basis. A 2010 study published by the US Food and Drug Administration (FDA) reported the average adult consumes about 300 mg caffeine/day, with teenagers consuming roughly one third of that amount. In quantities found in food and beverages, caffeine is unlikely to cause acute medical problems; however, a changing market in which energy drinks are not subject to FDA regulatory standards raises new concerns over caffeine-related health problems.

Chemical structure of caffeine. Chemical structure of caffeine.

In 1989, the US Food and Drug Administration (FDA) limited the amount of caffeine in OTC products to a maximum of 200 mg/dose. The ingestion of such concentrated sources of caffeine is the general cause of acute caffeine toxicity. See the image below for caffeine equivalents of common products.

Caffeine content of various foods, beverages, medi Caffeine content of various foods, beverages, medications, and supplements. Caffeine content is approximate for brewed beverages and chocolate).

Caffeine has differing CNS, cardiovascular, and metabolic effects based on the quantity ingested. Average doses of caffeine (85-250 mg, the equivalent of 1-3 cups of coffee) may result in feelings of alertness, decreased fatigue, and eased flow of thought. High doses (250-500 mg) can result in restlessness, nervousness, insomnia, and tremors. In high doses, caffeine can cause a hyperadrenergic syndrome resulting in seizures and cardiovascular instability.

Because caffeine overdoses, intentional or unintentional, are relatively common in the United States, physicians and other medical personnel must be aware of caffeine toxicity to recognize and treat it appropriately.

FDA regulation on caffeine depends on whether the product is classified as a food, drug, or dietary supplement. In 1989, the FDA limited the amount of caffeine in over-the-counter products to a maximum of 200 mg/dose. Caffeine is present in concentrated forms in over-the-counter products, such as alertness-promoting medications (eg, NoDoz, Vivarin), menstrual aids (eg, Midol), analgesics (eg, Excedrin, Anacin, BC Powder), and diet aids (eg, Dexatrim). Caffeine is also a component of prescription medications (eg, Fioricet, Cafergot) and herbal preparations.

In cola beverages, caffeine is permitted by the FDA for flavor use at a 0.02% (0.2 mg/mL) concentration, equivalent to 20 mg in a 100-mL beverage or 71 mg in a 12-ounce beverage (Code of Federal Regulations, title 21, sec. 182.1180).[1] Because caffeine is not considered a nutrient, the FDA does not require manufacturers to label the amount of caffeine present in food and beverages, although caffeine must be listed as an ingredient if the manufacturer adds it to their product.[2]

Although caffeine is found in food and over-the-counter products, more than 97% of caffeine consumed by adults and teenagers comes from beverages, including coffee, tea, cola-products, and energy drinks.[3] Unlike cola-beverages, energy drinks and shots are typically classified as dietary supplements; thus, individuals who consume these products are likely unaware of how much caffeine they are actually consuming.[2]

The caffeine content of dietary supplements is virtually unregulated by the FDA. Prior to the Dietary Supplement Health and Education Act (DSHEA) of 1994, dietary supplements were subject to the same regulatory requirements as other foods; however, after DSHEA, the safety of dietary supplements became the sole responsibility of manufacturers. Consequentially, there are no limitations on the amount of caffeine in dietary supplements and manufacturers are not required to list the caffeine content of their products.[4] The ingestion of concentrated sources of caffeine is the general cause of acute caffeine toxicity.

Table 1. Reported Caffeine Content of Common Items[3] (Open Table in a new window)

Item Amount Caffeine Content, mg
M & M Milk Chocolate Candies 47.9 g (1 bag) 7
Coca-Cola Classic 12 oz 35
Fiorinal/Fioricet 1 tablet 40
Brewed black tea, generic 8 oz 45-74
Red Bull Regular 8.4 oz 80
Brewed coffee, generic 8 oz 57
Midol 1 Gel Cap 60
No Doz 1 tablet 100
Regular 5-Hour Energy 2 oz 138
Rockstar 16 oz 160
Monster Energy 16 oz 160
Espresso, generic 1 oz 170
Vivarin 1 tablet 200
NOS 16 280
Starbucks Tall Americano 16 330

 

The rising popularity of caffeinated energy drinks over the past decade has raised new concerns about their impact on public health. As illustrated above, energy drinks contain substantially more caffeine than conventional cola beverages, with caffeine content ranging from 75-300 mg per serving. Many also contain caffeine-containing ingredients such as guarana, kola nut, or yerba mate. Consequentially, they may contain more caffeine than reported in Table 1 above.[5] These energy drinks are also sold in larger sizes (16-23.5 fl oz). It is not uncommon for individuals to consume multiple caffeinated beverages over the course of a day.

Caffeine has differing CNS, cardiovascular, and metabolic effects based on the quantity ingested. Average doses of caffeine (85-250 mg, the equivalent of 1-3 cups of coffee) may result in feelings of alertness, decreased fatigue, and eased flow of thought. High doses (250-500 mg) can result in restlessness, nervousness, insomnia, and tremors. In high doses, caffeine can cause a hyperadrenergic syndrome resulting in seizures and cardiovascular instability.

Because caffeine overdoses, intentional or unintentional, are relatively common in the United States, physicians and other medical personnel must be aware of caffeine toxicity to recognize and treat it appropriately.

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Pathophysiology

Caffeine, a methylxanthine, is closely related to theophylline. Caffeine is rapidly and completely absorbed from the GI tract; it is detectable in the plasma 5 minutes after ingestion, with peak plasma levels occurring in 30-60 minutes. The volume of distribution in adults is approximately 0.5 L/kg. Caffeine is primarily metabolized by the cytochrome P450 (CYP) oxidase system in the liver. The plasma half-life of caffeine varies considerably from person to person, with an average half-life of 5-8 hours in healthy, nonsmoking adults. Caffeine clearance is accelerated in smokers; clearance is slowed in pregnancy, in liver disease, and in the presence of some CYP inhibitors (eg, cimetidine, quinolones, erythromycin). In addition, the hepatic enzyme system responsible for caffeine metabolism can become saturated at high levels, resulting in a marked increase in serum concentration with small additional doses.

Various mechanisms mediate the effects of caffeine in the human body. Caffeine directly stimulates respiratory and vasomotor centers of the brain and acts as an adenosine antagonist, resulting in peripheral vasodilatation and CNS stimulation. Caffeine is a potent releaser of catecholamines (norepinephrine and, to a lesser extent, epinephrine) that increases cardiac chronotropic and inotropic activity, bronchodilation, and peripheral vasodilatation. Caffeine is also a phosphodiesterase inhibitor. However, because extremely high concentrations of caffeine are required to inhibit this enzyme, whether this effect contributes to the clinical effects of caffeine in vivo is unknown.

In addition to its cardiovascular effects, caffeine induces a number of metabolic changes, including hyperglycemia (by stimulating gluconeogenesis and glycogenolysis), increased renal filtration, ketosis, and hypokalemia. Caffeine is a potent stimulator of gastric acid secretion and GI motility.

Death from caffeine toxicity is rare, but it has been reported due to dysrhythmias, seizures, and aspiration of emesis. Oral doses of caffeine greater than 10 g can be fatal in adults. The average daily adult intake should generally be less than 500 mg/d.

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Frequency

United States

Although caffeine poisoning is a relatively common toxicologic emergency in the United States, the number of incidences has steadily increased in the past decade . The Substance Abuse and Mental Health Services Administration (SAMHSA) reported a jump in the number of emergency department visits involving energy drinks, increasing roughly 10-fold from 2005 (1128 visits) to 2008 and 2009 (16,053 and 13, 114 visits, respectively). More than half of the visits made by patients ages 18-25 years involved the combination of energy drinks with alcohol or other drugs.[6]

In 2010, American Association of Poison Control Centers' National Poison Data System (AAPCC-NPDS) added “Energy Drinks” to its annual reports, which included several subcategories, including “Caffeine Containing,” ”Caffeine Only,” ”Ethanol and Caffeine Containing.” and “Ethanol and Caffeine Only.”

Table 2. Caffeine-Related Poisonings Reported to the NPDS From 2009-2011 (Open Table in a new window)

Category Single Exposures Deaths
2009 2010 2011 2009 2010 2011
Energy Drinks            
Caffeine containing - 139 548 - 0 1
Caffeine only - 169 1062 - 0 0
Ethanol and caffeine containing - 76 131 - 0 0
Ethanol and caffeine only - 2 3 - 0 0
             
Pheylnolamine and caffeine combinations (diet aid) 10 22 11 0 0 0
             
Caffeine 3433 3328 2655 0 0 0

As of March 2013, the AAPCC Web site had an alert urging the public to use caution with energy drink products. The alert also states there were 3150 energy drink exposures in 2012, though the annual AAPCC-NPDS report for 2012 has yet to be released.[7] Caffeinated alcohol beverages were another public health concern; however, the FDA banned their sales in 2010. In spite of the ban, mixing alcohol with energy drinks is still common practice and popular. As a result, it appears that the number of poisonings due to caffeinated energy drinks is continuing to rise.[5] It is very important for the physician to inquire about co-ingestion of caffeine-containing drinks when obtaining history for possible drug overdose or alcohol poisoning.

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Mortality/Morbidity

Death is an uncommon result of caffeine poisoning. According to the AAPC-NPDS, there was only a single death related to caffeine from 2009-2011. However, a separate report published by the FDA’s Center for Food Safety and Applied Nutrition (CFSAN) Adverse Event Reporting System (CAERS) cited the number of deaths related to caffeinated energy drinks between 2004 and 2010 at a much higher number. In total, they report 16 deaths related solely to Monster, 5-Hour Energy, and Rockstar.[8] In 2010, the FDA received several reports of possible energy drink related fatalities.[9]

On a related note, many manufacturers are now changing the classification of their products from “dietary supplements” to “beverages,” which means that companies will no longer have to report potential cases linking their products to injury or death to the FDA.[10]

Death due to caffeine-related dysrhythmias, seizures, and aspiration of emesis has been reported.

Oral doses of caffeine greater than 10 g can be fatal in adults.

Race

Caffeine is the most commonly used drug in the world, and its use is prevalent in essentially all races and ethnic groups throughout the world. No scientific data have demonstrated that the outcomes of caffeine exposure differ on the basis of race.

Sex

No scientific data have demonstrated that the outcomes of caffeine exposure differ on the basis of sex. There is not a recommended daily allowance for caffeine but the American Dietetic Association posits that women of reproductive age should consume no more than 300 mg of caffeine per day.[11]

Age

Whether or not the effects of caffeine on adults can be generalized to children is unclear; however, studies suggest children are differentially affected by caffeine. One study comparing the effects of caffeine in men and boys found that the same dose of caffeine raised blood pressure in both groups but only decreased heart rate in boys. They also found that boys exhibited increased motor activity and speech rates and decreased reaction time compared with men.[12]

Another study found that an intake of 5 mg/kg body weight leads to elevated blood pressure and lower heart rate, without concomitant changes in energy metabolism in children aged 9-11 years. This amounts to 160 mg caffeine/day in a 10-year-old child weighing 30 kg, which is equivalent to the caffeine content of a single 16-oz Monster or Rockstar energy drink. This is consistent with data from an earlier report by the European Food Safety Authority’s (EFSA) Scientific Committee on Food, stating that an intake of 5 mg caffeine/kg body weight is sufficient to increase arousal, irritability, nervousness, and anxiety in children, especially if they do not normally consume caffeine.[13]

In 2011, the AAPCC-NPDS reported the greatest number of caffeine poisoning cases were in children younger than 5 years (1055), followed by individuals aged 20 years or older (938), then ages 13-19 years (428) and ages 6-12 years (83). Similar trends are observed for caffeinated energy drinks, with which children younger than 5 years have the highest reported poisonings.

Additional age-related concerns arise from the fact that many energy drinks are marketed toward youth and youth-related activities, such as extreme sports. Students and athletes often drink them to enhance performance. A recent survey of 496 college students found that 51% of those surveyed drank more than 1 energy drink per month, with the majority of students actually several drinking energy drinks per week. The main impetus was the desire for increased energy and concentration, with the most common complaint being insufficient sleep or a disruption in their regular sleep cycles.[14]

Table 3. Energy Drink Exposure (Open Table in a new window)

Item No. Exposures (single) Exposures (5) Exposures (6-12) Exposures (12-19) Exposures (20)
Energy Drinks          
Caffeine containing 548 227 60 141 111
Caffeine only 1062 582 91 128 226
Ethanol and caffeine containing 131 15 5 78 28
Ethanol and caffeine pnly 3 1 0 0 2
           
Pheylnolamine and caffeine combinations (diet aid) 11 5 1 1 4
           
Caffeine 2655 1055 83 428 938

Serum caffeine clearance is greatly decreased during the first 6 months of life.

Caffeine doses of 78 mg/kg have caused serious adverse effects in young children.

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Contributor Information and Disclosures
Author

David Yew, MD Assistant Clinical Professor, Department of Surgery, University of Hawaii, John A Burns School of Medicine; Medical Director and Flight Physician, Hawaii Life Flight, AirMed International

David Yew, MD is a member of the following medical societies: American College of Emergency Physicians, Air Medical Physician Association

Disclosure: Nothing to disclose.

Coauthor(s)

China N Byrns Department of Cell and Molecular Biology, University of Hawaii at Manoa

China N Byrns is a member of the following medical societies: Phi Beta Kappa

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John G Benitez, MD, MPH Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

John G Benitez, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Undersea and Hyperbaric Medical Society, Wilderness Medical Society, American College of Occupational and Environmental Medicine

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

James E Keany, MD, FACEP Associate Medical Director, Emergency Services, Mission Hospital Regional Medical Center, Children's Hospital of Orange County at Mission

James E Keany, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American College of Sports Medicine, California Medical Association

Disclosure: Nothing to disclose.

Acknowledgements

Jeffrey T Laczek, MD Gastroentology Fellow, Walter Reed Army Medical Center

Disclosure: Nothing to disclose.

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Caffeine content of various foods, beverages, medications, and supplements. Caffeine content is approximate for brewed beverages and chocolate).
Chemical structure of caffeine.
Table 1. Reported Caffeine Content of Common Items [3]
Item Amount Caffeine Content, mg
M & M Milk Chocolate Candies 47.9 g (1 bag) 7
Coca-Cola Classic 12 oz 35
Fiorinal/Fioricet 1 tablet 40
Brewed black tea, generic 8 oz 45-74
Red Bull Regular 8.4 oz 80
Brewed coffee, generic 8 oz 57
Midol 1 Gel Cap 60
No Doz 1 tablet 100
Regular 5-Hour Energy 2 oz 138
Rockstar 16 oz 160
Monster Energy 16 oz 160
Espresso, generic 1 oz 170
Vivarin 1 tablet 200
NOS 16 280
Starbucks Tall Americano 16 330
Table 2. Caffeine-Related Poisonings Reported to the NPDS From 2009-2011
Category Single Exposures Deaths
2009 2010 2011 2009 2010 2011
Energy Drinks            
Caffeine containing - 139 548 - 0 1
Caffeine only - 169 1062 - 0 0
Ethanol and caffeine containing - 76 131 - 0 0
Ethanol and caffeine only - 2 3 - 0 0
             
Pheylnolamine and caffeine combinations (diet aid) 10 22 11 0 0 0
             
Caffeine 3433 3328 2655 0 0 0
Table 3. Energy Drink Exposure
Item No. Exposures (single) Exposures (5) Exposures (6-12) Exposures (12-19) Exposures (20)
Energy Drinks          
Caffeine containing 548 227 60 141 111
Caffeine only 1062 582 91 128 226
Ethanol and caffeine containing 131 15 5 78 28
Ethanol and caffeine pnly 3 1 0 0 2
           
Pheylnolamine and caffeine combinations (diet aid) 11 5 1 1 4
           
Caffeine 2655 1055 83 428 938
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