Caffeine Toxicity: Practice Essentials, Background, Pathophysiology http://emedicine.medscape.

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

OVERVIEW

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.

View Media Gallery

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

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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

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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.

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.

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Chemical structure of caffeine.

View Media Gallery

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, medications, and supplements. Caffeine content is approximate
for brewed beverages and chocolate).
View Media Gallery

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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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

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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.

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

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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.

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

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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.

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

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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)

No.
Exposures Exposures Exposures Exposures
Item Exposures
(5) (6-12) (12-19) (20)
(single)

Energy Drinks

Caffeine
548 227 60 141 111
containing

Caffeine only 1062 582 91 128 226

Ethanol and
caffeine 131 15 5 78 28

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containing

Ethanol and
3 1 0 0 2
caffeine pnly

Pheylnolamine
and caffeine
11 5 1 1 4
combinations
(diet aid)

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.

Clinical Presentation

References

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39. Turley KR, Gerst JW. Effects of caffeine on physiological responses to exercise in young
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Media Gallery

Caffeine content of various foods, beverages, medications, and supplements. Caffeine

content is approximate for brewed beverages and chocolate).

Chemical structure of caffeine.

of 2

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Tables

Table 1. Reported Caffeine Content of Common Items [3]

Table 2. Caffeine-Related Poisonings Reported to the NPDS From 2009-2011
Table 3. Energy Drink Exposure

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

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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

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Caffeine Toxicity: Practice Essentials, Background, Pathophysiology http://emedicine.medscape.com/article/821863-overview

Caffeine 3433 3328 2655 0 0 0

Table 3. Energy Drink Exposure

No.
Exposures Exposures Exposures Exposures
Item Exposures
(5) (6-12) (12-19) (20)
(single)

Energy Drinks

Caffeine
548 227 60 141 111
containing

Caffeine only 1062 582 91 128 226

Ethanol and
caffeine 131 15 5 78 28
containing

Ethanol and
3 1 0 0 2
caffeine pnly

Pheylnolamine
and caffeine
11 5 1 1 4
combinations
(diet aid)

Caffeine 2655 1055 83 428 938

Back to List

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

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Caffeine Toxicity: Practice Essentials, Background, Pathophysiology http://emedicine.medscape.com/article/821863-overview

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

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Disclosure: Nothing to disclose.

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