Gurpreet Singh, M.D., Pramod Kayathi, M.D., Vivek C. Shah, M.D., Steven Lippmann, M.D.

Introduction
Caffeine is a naturally occurring psychoactive substance found in many different plants. It is a powerful stimulant, marketed as a dietary supplement, and occurs in beverages such as coffee, tea, cola, energy drinks or pills, and chocolate products, etc.  Unlike some other psychoactive drugs, caffeine is legal and unregulated. About  80% of American adults ingest caffeinated products at an average intake of approximately 200mg per day (1).  Caffeine utilization at under 500mg is commonly considered to be safe, and there is documented safety at 300mg or below per day (2).

Pharmacology / Availability
Caffeine, a methyl-xanthine, is a central nervous system stimulant that increases mental alertness and diminishes drowsiness. It also acts as a diuretic and appetite suppressant. Caffeine is an adenosine receptor antagonist, which leads to stimulation of vasomotor, medullary vagal, and respiratory centers. In brain, adenosine exhibits inhibitory actions, so blockade of adenosine receptors promotes the release of neurotransmitters like monoamines and acetylcholine, which yields the stimulatory effect. It also potentiates the release of catecholamines, which results in positive chronotropic and inotropic cardiac effects, bronchodilation, and peripheral vasodilation.

Caffeine enhances concentration, elevates mood, and promotes wakefulness. By decreasing the perception of fatigue and pain, it augments athleticism. It is thus utilized to increase energy, alertness, motivation, physical performance, and weight loss. Non-beverage forms of caffeine utilized to attain these goals commonly include caffeine pills.

More recently, potent powdered versions have become available, especially over the internet. It is often marketed as a dietary supplement. The powder form is so concentrated that a teaspoon often contains between 1600 – 3200mg of caffeine. The recommended single serving is one sixteenth of a teaspoon or about 100-200mg (3). Since this is a small amount, it is difficult to measure at home and dosage is easily exceeded. Some people escalate these serving guidelines. Thus, overdose with caffeine powder becomes an important clinical issue.

Toxicity
Doses exceeding 600mg can cause significant side-effects. Single doses of >5,000mg can be lethal (4). Since one teaspoon of caffeine powder can contain 3,200mg of caffeine, the occurrence and risk for overdosing and toxicity are significant (3).  Caffeine is hepatically metabolized by the cytochrome P-450 system, so persons with liver disease and those taking cytochrome inhibitors like cimetidine, erythromycin, and oral contraceptives, etc. have an increased caffeine intoxication risk. Since tobacco smoke is an enzyme inducer, smoking increases caffeine clearance, and cessation predisposes to toxicity.

Caffeine intoxication can present in mild degrees with anxiety, insomnia, tremors or muscle twitches, palpitations, headache, diarrhea, thirst, and/or dizziness. As the toxicity increases, more severe manifestations include rapid speech, excitability, agitation, hallucinations, convulsions, trouble breathing, arrhythmias, and chest pain. Rhabdomyolysis is reported following caffeine intoxications (5).  Large quantities of caffeine are ill-advised during pregnancy to promote fetal and maternal health (6). During lactation, caffeine is excreted in breast milk and might result in toxicity to babies; so lactating mothers should avoid caffeine products.

With higher quantities of caffeine ingestion, death may result. Lethality is reported even at amounts under 5,000mg, if ingested with certain other drugs or to persons in frail health. Reaching dangerous levels of toxicity with routine beverages is rare; however, the pills and especially the powdered forms have considerably greater dangerousness. Death by caffeine overdose is documented (3). The pill and powdered versions are a medical concern.

Management
Management of caffeine toxicity includes symptomatic measures. Laboratory conformation of serum caffeine concentrations are obtained at clinical discretion. In acute treatment, the goal is to eliminate caffeine from the patient’s body. Individuals with mild symptoms are observed with electrocardiographic monitoring and hydrated. For moderately severe presentations, expedite the elimination of caffeine with activated charcoal and/or gastric lavage. More dangerous toxicities demand hemodialysis or peritoneal dialysis.

References
1.    Persad L. Energy Drinks and the Neurophysiological Impact of Caffeine. Front Neurosci. 2011; 5: 116.  DOI: 10.3389/fnins.2011.00116
2.    International Food Information Council Review. Caffeine & Health: Clarifying The Controversies. Retrieved from – http://www.foodinsight.org/Content/3147/Caffeine_v8-2.pdf
3.    New York Post. Powdered caffeine scrutinized after prom king dies. Retrieved from- http://nypost.com/2014/07/19/powdered-caffeine-scrutinized-after-prom-king-dies/
4.    Kerrigan S, Lindsey T. Fatal caffeine overdose: two case reports. Forensic Sci Int. 2005; 153(1):67-69. DOI: http://dx.doi.org/10.1016/j.forsciint.2005.04.016
5.    Kamijo Y, Soma K, Asari Y, et al. Severe rhabdomyolysis following massive ingestion of oolong tea: caffeine intoxication with coexisting hyponatremia. Vet Hum Toxicol. 1999; 41(6):381-383. Retrieved from – http://www.ncbi.nlm.nih.gov/pubmed/10592946
6.    Hey E. Coffee and pregnancy. BMJ. 2007; 334(7590): 377. DOI:  10.1136/bmj.39122.395058.80