17
caffeine dependence intoxication and toxicity

The recognition of syndromes of intoxication, withdrawal, and dependence suggests that caffeine is like other psychoactive drugs.

—Roland R.Griffiths, JAMA, 1994

A typical lethal dose of caffeine is 10 grams. A shot of espresso has 100 mg. So it ought to take a nice round 100 shots, or say 50 double cappucinos, to get to that big café in the sky.

—Excerpt from posting in alt.drugs.caffeine, February 1996

Progress in understanding drug dependence has been impeded by a host of nonscientific moral, emotional, and legal factors. Fear of lethal drugs of abuse, such as heroin and cocaine, has clouded what might otherwise have been a neutral and relatively straightforward evaluation of the nature and extent of the habit-forming properties of less dangerous agencies, such as marijuana and caffeine, engendering confusion and doing little to encourage much-needed studies.

The word “dependence” is used in scientific literature in at least two distinct ways. “Physical dependence” is defined by the occurrence of a withdrawal syndrome after cessation of the use of a substance. Opium, cigarettes, and coffee each contain a psychoactive drug producing physical dependence: morphine, nicotine, and caffeine, respectively. “Clinical dependence syndrome” usually includes physical dependence, but also involves a pattern of pathologic behavior. Drugs that can support a clinical dependence syndrome are usually considered drugs of abuse. A heroin addict, whose behavior is deleteriously conditioned by his need to acquire the drug, exhibits clinical dependence syndrome. In contrast, a cancer patient under extended treatment with opioids will demonstrate physical dependence, but would probably not display any other symptoms of clinical dependence.

Caffeine unquestionably supports a physical dependence, as proved by the withdrawal symptoms associated with its abrupt discontinuation. It also has several additional characteristics in common with drugs that support a clinical dependence syndrome. These characteristics include both caffeine’s ability to improve people’s moods, self-confidence, and energy and what researchers call its ability to act as a reinforcer, or what in laymen’s terms might be phrased as “the more you get, the more you want” factor. Yet despite the reasonableness of the hypothesis and considerable anecdotal evidence, it has been demonstrated only recently that there actually are users whose pattern of caffeine consumption merits a diagnosis of clinical dependence syndrome. In the American Psychiatric Association’s DSM-IV, caffeine was the only psychoactive substance listed as supporting a physical dependence but not a clinical dependence syndrome. If research in this area continues, caffeine will probably lose this distinction by the time of the publication of the DSM-V.


Physical Dependence and Withdrawal

As early as 1893, a researcher, N.Bridge, reported on a series of patients presenting a variety of symptoms he attributed to the use of coffee or tea, concluding that eliminating caffeine from their diets could be beneficial.1 However, he warned that patients who terminated their caffeine use abruptly were at risk for developing a severe headache. In consequence he recommended a regimen similar to the one favored by physicians today, reducing coffee consumption gradually over a week or more.

Headaches associated with the abrupt cessation of caffeine use have been experienced by millions in their daily lives and constitute the most typical feature of caffeine withdrawal and the most immediate evidence that caffeine supports a physical dependence. Other common symptoms of caffeine withdrawal, some of which the reader may have experienced when unable to enjoy his accustomed morning brew, can include:

Additional reported symptoms are increased depression or anxiety or impaired psychomotor performance.

In a detailed, carefully controlled study in 1986, Roland Griffiths provided a more detailed schedule of caffeine withdrawal symptoms than had been available previously. He found that caffeine withdrawal generally begins within twelve to twenty-four hours after discontinuing caffeine use. It generally peaks within twenty-four to fortyeight hours, and it lasts from about two days to a week.2 As with many of the manifestations of caffeine use, there is considerable variability both between people and within the same person in the effects, duration, and severity of caffeine withdrawal.

The single best estimate of the incidence of caffeine withdrawal symptoms in a clinical setting was provided in a 1992 study3 of more than sixty normal adults with low to moderate daily caffeine consumption, an average of 235 mg a day, or the equivalent of about two cups of coffee. This was a double-blind study, that is, one in which neither the researcher nor the subject knows who is receiving caffeine and, if so, in what quantities. More than 50 percent of the participants who did not receive caffeine had moderate to severe headaches, about 10 percent had symptoms associated with anxiety and depression, and about another 10 percent had significantly high ratings of fatigue. Nearly 15 percent used analgesics for aches and pains occasioned by withdrawal.

What is it about the cessation or relative decrease in the intake of caffeine that generates the range of physical and psychological problems listed above? Caffeine withdrawal is probably caused by the cessation of adenosine antagonism, which is caffeine’s chief pharmacological mechanism of action. When caffeine use ceases, caffeine’s supression of adenosine ceases, and it is natural that the abstainer should experience sluggishness, torpor, difficulty in concentrating, and depression. In addition, the prior use of caffeine may have resulted in a compensatory increase in the number of adenosine receptor sites, intended by the body to help restore the level of adenosine to that which existed before regular caffeine use.4 Specifically, caffeine withdrawal symptoms may be partially explained by the decrease in central nervous system activity and the increase in cerebral blood flow associated with increased adenosine activity. The results of an EEG study which demonstrated increased alpha and beta voltage in the frontal-central cortex during caffeine withdrawal has been interpreted as being consistent with the hypothesis that caffeine withdrawal may be due to cerebral blood flow changes.5

The most common and notorious feature of caffeine withdrawal is the headache, which, consistently with the above analysis, has been described as a feeling of cerebral fullness. Typically it is a generalized throbbing headache that can, in extreme cases, be accompanied by flulike symptoms such as nausea and vomiting. The caffeine withdrawal headache is worsened with physical exercise and, not surprisingly, is relieved by caffeine. The withdrawal headaches usually abate within two to four days, although some subjects continue reporting sporadic headaches for ten days or more after cessation of caffeine use. It should be noted that several reports have concluded that sudden extreme increases in caffeine or coffee consumption can also produce headaches.

The caffeine withdrawal headache has frequently been observed in a hospital setting. One registered nurse at a hospital reports what turns out a common pre- and post-operative observation of caffeine withdrawal: “When I worked in an ambulatory surgery setting, many patients who were NPO [not to eat or drink anything] and therefore [had gone] without their usual cup of caffeine since the night before would experience quite severe headaches if they were still NPO by 11 A.M. or so. For most routine caffeine users, the first thing they said in the recovery area was ‘Can I get some coffee?! I have a headache!’ The phenomenon occurred often enough that even nurses new to the area caught on pretty quickly, and widespread enough for it to be a topic of informal conversation during nationwide nurses’ conventions!”6 Recently some surgical teams have given patients caffeine intravenously to avoid headaches and other withdrawal symptoms during the operation and recovery periods.

This complex of caffeine withdrawal symptoms is compellingly reminiscent of what might be termed the “addict’s flu,” the generalized withdrawal symptoms common to many addictive drugs, notably including heroin and other opiates and barbiturates. The symptoms of withdrawal from these drugs are typically much more severe than those exhibited in the flulike symptoms of caffeine withdrawal, but the pattern of symptoms, including fatigue, aches and pains, irritability, running nose, perspiration, and cravings for the drug, are otherwise identical.

Several studies have found that both the likelihood of caffeine withdrawal and its severity increase as the daily dose attained before cessation is increased. However, it has been shown that caffeine withdrawal can occur after discontinuation of surprisingly low regular doses of caffeine, as little as 100 mg per day, which is the equivalent of about one cup of coffee or two cans of cola.

There is one report of eight infants with suspected caffeine withdrawal born to mothers who had moderate to heavy caffeine consumption during their pregnancies (200–1,800 mg a day). The infants’ symptoms, including irritability, jitteriness, and vomiting, began an average of about twenty hours after birth and then abated completely.7

The possible onset of caffeine withdrawal makes it advantageous for caffeine users to plan ahead as they approach circumstances where it may be necessary or desirable to eliminate caffeine. Because many general medical conditions can have signs and symptoms that are similar to caffeine withdrawal, it is necessary to systematically exclude other explanations for the symptoms. An adequate differential diagnosis should encompass conditions as diverse as viral illnesses, sinus conditions, migraine or tension headaches, other drug withdrawal states, such as amphetamine or cocaine withdrawal, and idiopathic drug reactions.


Clinical Dependence Syndrome

Opinions vary among psychologists and psychiatrists about whether caffeine should be branded, along with heroin, cocaine, and nicotine, as a drug of abuse, that is, as an agent supporting a clinical dependence syndrome. The majority opinion, supported in studies by Strain, Griffiths, and others at the Department of Psychiatry and Behavioral Sciences, the Johns Hopkins University School of Medicine, and reported in JAMA in 1994,8 provides clinical evidence supporting a caffeine clinical dependence syndrome similar to the dependence syndromes of heroin and cocaine but milder.9 A minority of professionals, citing the modest and transient discomforts of caffeine withdrawal, assert that caffeine has little in common with dangerous psychoactive drugs of abuse and should not be described as supporting a clinical dependence syndrome.10

The best opinion seems to be an amalgam of the two. On the one hand, there is no doubt that caffeine, like cocaine, has all the hallmarks of a drug that supports a clinical dependence syndrome: It produces the subjective effects of euphoria, energy, and self-confidence; it demonstrates a “reinforcing effect,” that is, the capacity of a pharmacological agent to encourage sustained use; and, finally, as we have noted, it supports a physical dependence, including a developed tolerance and withdrawal symptoms on cessation.11 On the other hand, it is clear that caffeine’s subjective effects, reinforcing effects, and withdrawal symptoms are far less pronounced than the recognized drugs of abuse, such as cocaine, dextroamphetamine, or pentobarbital, and therefore, caffeine’s clinical dependence syndrome, if it indeed exists, cannot be uncritically equated with the clinical dependence syndromes of these other drugs.12

Extrapolating from a telephone survey of two hundred Vermont residents conducted by a group of researchers in 199213 (the only study using standardized psychiatric criteria to evaluate the prevalence of caffeine clinical dependence), and applying the estimate that more than 80 percent of all American adults consume caffeine daily, with an average consumption among users of nearly 300 mg a day, we could venture that, in the United States alone, 75 million people would fit the criteria for moderate caffeine clinical dependence syndrome. The average daily consumption and, therefore, the estimate of the levels of this dependence syndrome in other countries may be considerably higher.

So the question remains: Does caffeine, like cocaine, support compulsive use, that is, an habitual pattern of self-administration persisting despite untoward personal, health, economic, or social consequences and repeated attempts to discontinue taking it? It is very difficult to determine the extent to which the nearly universal use of caffeine, in some surveys reaching 92 to 98 percent of North American adults, is, in one researcher’s words, “due to its centrally mediated stimulus functions, rather than liking the taste of hot coffee, or the fact that drinking coffee is such a socially acceptable behavior.”14 Although anecdotal reports of the regular patterns of consumption engaged in by most caffeine users satisfy the criterion of habitual use, there is little evidence to help us decide whether the strength of the desire to persist in these patterns would satisfy the definition of compulsive behavior. Nevertheless, it remains a credible speculation that a minority of caffeine users consume caffeine compulsively, to the extent that they would find it difficult to reduce or eliminate it from their diet. Whatever the outcome of current studies, it is safe to assert that caffeine dependence, like other drug dependence syndromes, in all likelihood represents the interaction of social and cultural forces, of individual histories and predispositions operating at the same time as a psychoactive substance that produces pleasant mood-altering and reinforcing effects.


Is Caffeine a Drug of Abuse?

If asked to explain the nature of a drug of abuse, many people might answer, “I may not be able to define a drug of abuse, but I know one when I see one.” Consideration of patterns of drug use in other societies, however, may disturb such comforting smugness. As we saw in the Yemen, for example, the plant khat, which contains a very powerful stimulating, habituating, and intoxicating drug, is brewed into tea, much in the way we use caffeine, and is used by the great majority of both children and adults. Outside observers have frequently assumed that khat is a drug of abuse and that the Yemeni population suffers from an addiction problem, similar to Western problems with heroin and cocaine, that should be addressed by every available educational, social, and legal countermeasure. Most people who live in the Yemen, however, do not share this opinion. The same question arises for us in relation to caffeine: If an entire society accepts a pattern of drug use, is that use, by definition, a normal one?

Researchers attempting to determine whether caffeine should be branded a drug of abuse have suggested that the word “addiction” be restricted to those conditions in which physical dependence and clinical dependence syndrome both obtain. Hirsh asserted that an addictive drug was one that engenders a “compulsion” or “an over-whelming involvement that pervades the total life activity…to the exclusion of all other interests,”15 and concluded that caffeine, like other methylxanthines, was not addictive. R.R.Griffiths and colleagues have argued that to qualify as a drug of abuse a substance must have both reinforcing effects and produce harmful effects on the user and the society. Caffeine’s reinforcing effects make it a candidate to be considered as a drug of abuse, but, Griffiths cautions, its classification as such must await a fuller appraisal of its possible deleterious effects.16

i_Image1

Photograph of Russian brick tea money. (Courtesy of Chase Manhattan Archives)

i_Image3

Photograph of Russian brick tea money. (Courtesy of Chase Manhattan Archives)

Looking at the question from a different angle, we note that the remorseless metabolic and psychical demand for certain intoxicants combines with their portability to enable them to function as money in a black market. In fact, one hallmark of a psychoactive drug of abuse, therefore, is a history of its use as a medium of exchange. Opium, for example, is as good as money among black-market traders in Southeast Asia. Cocaine is like gold bullion to the cartel managers of South America. Similarly, caffeine-rich seeds, beans, and processed leaves have frequently served as mediums of exchange throughout the world. In some African countries, cola nuts are still used as money, the way the Maya, and other South Americans until the eighteenth century, used cacao beans. In China and Russia, dried tea leaves were pressed into bricks and used as currency. In Egypt and elsewhere among the Moslems, coffee was used as tender in the marketplace from the beginning of the sixteenth century.


Caffeine Intoxication: Too Much of a Good Thing

Many consumers of coffee, tea, and cola, never having entertained an association between caffeine and drug use, may be surprised to learn that the massive modern catalogue of psychiatric problems, the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), includes an entry for “Caffeine Intoxication,” which it describes either as an acute drug overdose condition, occurring after the ingestion of a large amount of caffeine, or as a chronic condition, otherwise known as “caffeinism” or “caffeism,” associated with the regular consumption of large amounts of caffeine.

There is nothing new about the awareness of caffeine intoxication, for it has been well described as a psychiatric disorder for more than a hundred years. Yet despite long-standing recognition, which perhaps began with the coining of the Arabic word “marqaha” or “caffeine high,” in the sixteenth century, there is, even today, little information available about its prevalence or incidence.

In 1896 J.T.Rugh17 reported the case of a traveling salesman who had resorted to excessive coffee consumption to maintain an intense pace of work and was troubled by nervousness, involuntary contractions in the arms and legs, a sense of impending danger, and sleep disturbance. Similar reports of caffeine intoxication first appear in medical literature from the middle of the 1800s, and the profile of common symptoms remains unchanged today. The most common are anxiety or nervousness, insomnia, gastrointestinal disturbances, irregular heartbeat, tremors, and psychomotor agitation. Other reported symptoms include excessive urination, headaches, diarrhea, and irregular breathing.

An interesting and unusual case was reported to JAMA early in 1914 by Otis Orendorff, M.D., of Canon City, Colorado. “A young miss, 18, an office clerk, of a slight, frail physique, had ordinary symptoms of asthenopia [eyestrain] for four years,” Orendorff wrote. She grew worse over a period of several months. Although tests were administered and full correction for her vision was provided, she experienced no relief. The patient was alternately exhilarated and depressed. She had memory lapses and maintained a “deportment with an indifference to the usual conventionalities and proprieties.” She had intermittent headaches, apparently not caused by work, but that increased when she attempted to read. She had insomnia at night but fell asleep at work. Her condition was getting serious. The physician was at his wits’ end, when the patient asked him “if there could be any danger in an overindulgence of Coca-Cola? stating that she drank from three to six glasses a day. In addition, she had two or three cups of strong coffee at mealtime, sometimes taking but little other nourishment.” He reports prompt improvement on curtailing her daily caffeine ingestion, concluding, “I feel that such a case is of interest from an ophthalmologic point of view and also because it indicates that the profession should be more alive to the pernicious influence in habit formation of some of the popular beverages served to young persons at public ‘slop’ fountains.”18

Unknown to the typical coffee or tea drinker, there exists a subterranean culture of undetermined extent in which caffeine is consumed with the fixed intention of inducing intoxication. That is, many people across the country and around the world regularly use large doses of caffeine to get high. In doing so, they frequently encounter many of the symptoms of toxicity, somatic and psychological, that we discuss in this

chapter. (See Appendix B, table 5, for the diagnostic criteria for caffeine intoxication from the Diagnostic and Statistical Manual of Mental Disorders.)

Internet news groups are electronic confraternities in which people who have generally never met each other post public messages, photographs, and even sound files pertaining to a common interest. If you access such newsgroups as “alt.drugs.caffeine” or “alt.coffee” on any given day, you are certain to find questions, comments, confessions, misgivings, and boasts regarding the use of large amounts of caffeine. Here are quotations from Internet postings, which are rife with misinformation and misspellings:


Q: What are some of the affects you’ve experienced when you suck down too much caffeine?

A: I actually seem to get less alert. Well, actually the only effect I get from overdosing on caffeine is severe nausea and vomiting. Man, I just go numb in my hands and feet and start shaking all over, as my mind and body go hyper. I can’t focus, can’t think straight. I go through oscillating emotional states, and I experience cold sweats, shaking, and sometimes tachycardia. I usually have oscillations from paranoid to psychotically calm and back again, along with racing thoughts, while getting slight muscle cramps.

A friend of mine snorted pharmaceutical grade caffeine once; he said it was extremely harsh on the nasal lining and not worth the buzz.


Q: I know a guy who once smoked a teabag and he claims that it gave him a buzz. Does anybody know if what he said is true?

A: Yes it works, i did it in england with the cheap tea they give you in a generic (low end) hotel, you just unfold the tea bag, you roll it up into something resembling a joint, and you light it, it is next to impossible to keep it lit though. oh it is the caffiene in it that gets you buzzed, the problem is that it goes away after about an hour and it leaves you with a bitch of a headache and some really bad cotton mouth.

• • •

I have used both caffeine and ephedrine together. It was related to one of my experiments, how to stay awake and keep going one whole week. I had to use quite a lot. I would say round 1500–2000 mg caffeine per day and around 200–300 mg ephedrine. Finally me and my head were quite mixed up. I was sleeping two hours a day and I kept this up for 19 days. I didn’t just think that I saw God, I thought I was God I only drink coffee now. Be careful.

It is clear that scientists have little hard data on which to base conclusions about the prevalence of caffeine intoxication. The uncertainty is exacerbated by the failure of some researchers to distinguish between chronic high caffeine consumption and caffeine intoxication, or similarly, the failure to distinguish between an isolated episode of caffeine intoxication and chronic intoxication. Because caffeine is the most widely used drug on earth, we can be sure that, sooner or later, both the prevalence and incidence of caffeine intoxication will be better characterized by applying the rigorous criteria for diagnosis, standardized assessments, and representative sampling techniques that have been applied to intoxicants such as alcohol, cocaine, and morphine.

Really heavy caffeine consumption has often been observed among institutionalized schizophrenics, as this curious letter, captioned “Coffee Eating in Chronic Schizophrenics,” from two psychiatrists to the American Journal of Psychiatry (July 1986) vividly attests:

Caffeinism, a psychophysiologic syndrome in DSM-III, is a clinically important syndrome per se, and as a co-diagnosis it may complicate the course of affective, anxiety, and thought disorders. The methylxanthines are the major pharmacoactive ingredient in many readily available caffeinated foods, beverages, and over-the-counter medications. To highlight a possibly important pattern of pathological consumption behavior that may produce caffeinism, we report three observations of coffee eating that occurred among chronic schizophrenic inpatients of a large state psychiatric hospital.

Mr. A, age 27, was frequently seen carrying around nearly empty jars of instant coffee, at which times he had an observable brown “mustache.” When asked, he volunteered that he and another patient pooled their money on Friday “paydays” to buy instant coffee, usually 6–10 oz. jars. Then, over several hours they would consume the coffee “for kicks” using plastic spoons. Nurses stated that they could tell when these patients had eaten coffee because they were more irritable and prone to “act up”; they also required more medications.

Ms. B, age 53, presented her physician with an obviously heart-felt and generous gift: a paper cup filled with instant coffee and plastic spoon “to help eat it.” She stated that she ate instant coffee when she could afford it and that she shared it with fellow patients. She said she “enjoyed the feeling” it gave her.

A third observation was of an incident in the breezeway between wards. A patient dropped a large jar of instant coffee. Despite the broken glass and the objections of staff, patients immediately crowded around and knelt down to scoop up the apparently precious powder, eating it directly off the floor.

These cases are not unique. Patients attest to the wide popularity of coffee eating in the hospital, where it seemed to be a shared social activity. Coffee eating is one of several examples of psychopharmacologically potent consumption behaviors that alter the clinical management of the psychotic patient. Such aberrant behaviors include excess coffee and tea ingestions, tobacco and marijuana abuse, and ethanol and self-induced water intoxication.19 Patients have co-abused coffee and trihexylphenidyl, a combination that produces hallucinations and euphoria.

These incidents are of clinical concern because caffeine is reported to exacerbate the clinical course of schizophrenia. Caffeine products may alter psychopharmacologic management by several mechanisms. First, the methylxanthines induce hepatic microsomal enzymes, which results in faster neuroleptic degradation. Second, patients may use caffeine to reverse the sedative side effects of antipsychotic drugs. Third, coffee (as a complex compound) forms insoluble precipitates with some antipsychotic medications, thus reducing their absorption. Fourth, the methylxanthines are adenosine antagonists that modulate CNS norepinephrine, serotonin, dopamine, and other neurotransmitters. Caffeine may thereby alter antipsychotic action at the neurotransmitter level. Coffee eating may represent a potentially malignant cause of caffeinism. Four ounces of instant coffee typically contain 5 g of caffeine, which in toxicological terms is about one-half the median lethal dose. The more general problem is that caffeinism among chronic hospitalized patients may be a widespread and clinically important problem.

Given the potent opiate receptor binding activity of coffee, we wonder whether naloxone might be worth investigation as a blocker of this aberrant consumption behavior.

John I.Benson, M.D., Augusta, GA
Joseph J.David, M.D., Charlottesville, VA

Another psychiatric problem associated with excessive caffeine consumption is delirium, which is sometimes present in cases of extreme caffeine intoxication. For example, caffeine-induced delirium has been reported in a man who chugged down large amounts of coffee, cola, and 800 mg of caffeine tablets while competing in the Iditarod sled dog race held between Anchorage and Nome, Alaska. He experienced tremor and alteration in his level of consciousness, anxiety, visual illusions and hallucinations, vertigo, and impaired memory consistent with an episode of delirium. While in this case and others delirium has been attributed to excessive caffeine use, the degree to which factors such as fatigue and sleep deprivation may have contributed to the delirium is not readily determinable. However, even though the redoubtable DSM-IV, the bible of psychiatric diagnosis, does not yet officially recognize caffeine as one of the agents that can produce a “substance intoxication delirium,” it seems probable that caffeine, like other psychoactive substances, should produce delirium if taken in sufficiently high doses.


Can Caffeine Kill?

If you take enough caffeine, it can kill you. The value generally accepted for a fatal overdose, and one given by pharmacology texts for fifty years, is about 10 grams for the average adult, about as much as in one hundred cups of coffee. In more precise clinical terms, the LD-50 of caffeine, that is, the lethal dosage for 50 percent of the population, is estimated at 10 grams for oral administration. However, the lethal dosage for any individual varies directly with body weight, and about 150 mg/kg to 200 mg/kg of caffeine is the usual estimate for the LD-50 for adult human beings. That is, those who weigh 150 pounds will have an LD-50 of at least 10 grams. However, because fatalities are very rare, and deaths have occurred at 5 to 50 grams, it is impossible to have confidence in this exact figure.

Acute toxic symptoms occur at levels as low as 50 mg/kg, equivalent to about 3.5 grams for a 150-pound person, about as much as in 35 cups of coffee. Even these levels are not usually attainable from dietary sources.20 Milder caffeine intoxication symptoms, including anxiety, insomnia, and gastrointestinal disturbances, can occur after a 150-pound man ingests as little as 250 mg, or about 3 mg/kg.

Researcher Jack James cites what may be the first account of caffeine poisoning, dating from 1883. In this description, a sixty-three-year-old man “survived an oral overdose of caffeine after developing various cardiovascular, CNS, and gastrointestinal symptoms.”21 Others have not been so fortunate. An account published in 1959 of a thirty-five-year-old woman who, after arriving at the hospital in a state of insulin shock, was accidentally injected with a caffeine solution instead of glucose,22 died after experiencing convulsions and respiratory arrest. Subsequent investigation determined that she had received 3.2 grams, raising her serum concentration of caffeine to 57 mg/kg.

Most of the cases where caffeine was the cause of death were the result of the accidental administration of caffeine by hospital staff. Typical examples are those of a fifteen-month-old boy and a sixty-one-year-old man, each given about 18 grams of caffeine orally. Another is a forty-five-year-old woman who was given 50 grams of caffeine instead of 50 grams of glucose.

In “A Fatal Ingestion of Caffeine,” a 1977 article in Clinical Toxicology, written by J.E.Turner and R.H.Cravey, of the Office of the Sheriff-Coroner, Toxicology Laboratory, Santa Ana, presents one of the rare caffeine-associated deaths. According to the authors, the thirty-four-year-old woman who was to die from a massive overdose of caffeine

complained of weakness and experienced episodes of vomiting. Upon retiring, her breathing became progressively labored, and she began to suffer convulsions. A rescue unit found her in coma. Upon arrival at the hospital, there was no audible heart beat, pulse, or breath sounds. She was in a state of acidosis (pH 6.8, arterial blood) with cyanosis about the neck and mouth. She had assumed an opisthotonic posture [a severe muscle spasm, in which the back arches and head and heels bend back, such as occurs in the final stages of tetanus]. Resuscitative efforts lasted one hour....

Autopsy revealed general congestion, particularly of the lungs, liver, and brain stem. Direct cause of death was attributed to pulmonary edema.23

Toxicological Findings after a Fatal Caffeine Overdose

Specimen                                                       Caffeine Content
Blood 10.6 mg/100 ml
Liver 11.6 mg/100 g
Kidney 12.4 mg/100 g
Brain 10.8 mg/100 g
Gastric 43 mg total, plus three partially undissolved tablets

Turner and Cravey, “A Fatal Ingestion of Caffeine,” Clinical Toxicology 10 (3): 341–44 (1977).

To comprehend the blood values of the deceased, consider that a 300 mg dose of caffeine, about as much as in two strong cups of coffee, result in a maximum blood concentration of about .5 mg/100 ml in a 200-pound adult, or less than 5 percent of the level found in this autopsy.

The survivor of what is probably the largest dose of caffeine on record is a twenty-one-year-old woman, estimated to have ingested a total of 106 grams, taken in the form of more than four hundred tablets, each containing 250 mg of caffeine. Despite an astonishing serum caffeine concentration of nearly 300 mg/100 ml, the patient was said to have shown “no residual neurological deficit” when discharged from the hospital four days later.24

Although people who consume caffeine are less likely to commit suicide than nonconsumers, there are outstandingly rare suicide attempts utilizing high doses of the drug, which, under extreme circumstances, may in fact prove fatal, and there have been at least two reports of suicides by caffeine overdose.25 Caffeine may be used to commit suicide so infrequently partially because few people know if it could kill them or how much it would take to kill them. The infrequency of accidental death may be a result of the emetic (purgative) effect of the drug. If there is evidence that a patient has significantly overdosed on caffeine, it should be treated as a medical emergency requiring intensive monitoring, symptomatic treatment for rapid or irregular heartbeat and seizures, aspiration of the stomach, and assessment of the serum caffeine level. Serum readings of more than 1 milligram per milliliter are generally considered toxic. Caffeine overdose has also been treated successfully with hemoperfusion, or flushing the blood supply clean with fluids.

Because infants and young children are much more vulnerable to the toxic effects of caffeine than adults, even when the discrepancies in their body weights have been factored out, researchers say that in infants 40 mg/ml is probably toxic.26 There is a case of a child who died from orally ingesting less than 5.5 grams, or the equivalent of about five cups of coffee.27

Finally, the habit of smoking cigarettes must be mentioned again in relation to caffeine toxicity. There is an unholy bond between the habits of smoking cigarettes and drinking coffee. Although the precise figures vary, every survey indicates that a higher percentage of smokers drink coffee regularly than do non-smokers and that of regular coffee drinkers, smokers drink more of it than do non-smokers. We have noted repeatedly how variable the kinetic profile, or speed of metabolic passage, of caffeine can be among different people or in the same person at different times. Most people do not realize, however, that giving up cigarettes causes a profound slowing of caffeine’s half-life, creating a toxic hazard for people who continue their previous levels of caffeine intake, unaware that, if they are no longer smoking, their coffee or tea will have a greater and more sustained effect on them than they had become accustomed to.