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Journal of Analytical Toxicology, 2017;41:167–172
doi: 10.1093/jat/bkx011
Advance Access Publication Date: 18 February 2017
Review
Review
Review of Caffeine-Related Fatalities along
with Postmortem Blood Concentrations
in 51 Poisoning Deaths
Alan Wayne Jones*
Department of Clinical Pharmacology, Faculty of Medicine, University of Linköping, Linköping, Sweden
*Author to whom correspondence should be addressed. Email: wayne.jones@liu.se
Abstract
Publications reporting concentrations of caffeine in postmortem blood were reviewed if the cause of
death was attributed to overdosing (poisoning) with drugs. Age and gender of the deceased, the
manner of death (accident, suicide or undetermined) and types of co-ingested drugs were evaluated
in relation to the concentrations of caffeine in blood (N=51). The mean age (±SD) of the victims was
39 ±17.8 years (range 18–84 years) and most were female (N=31 or 61%). The difference in mean
age of males (42 ±17.2 years) and females (37 ±18.3 years) was not statistically significant (t=0.811,
P=0.421). The mean (±SD), median and range of caffeine concentrations in postmortem blood were
187 ±96 mg/L (180 mg/L) and 33–567 mg/L, respectively. The median concentration of caffeine in
males (161mg/L) was not significantly different from that of females (182mg/L), z=1.18, P=0.235.
There was no correlation between the age of the deceased and the concentration of caffeine in post-
mortem blood (R
2
=0.026, P>0.05). Manner of death was classified as suicide in 51% of cases
(median blood–caffeine 185 mg/L), accidental in 16% (median 183 mg/L) or undetermined in 33%
(median 113 mg/L). The median concentration of caffeine in blood was lower when manner of death
was undetermined compared with suicide or accidental (P=0.023). Although other drugs, including
ethanol, antidepressants, antipsychotics, benzodiazepines and/or ephedrine, were often identified in
postmortem blood, the predominant psychoactive substance was caffeine. The deceased had
ingested caffeine in tablet or powder form and it does not seem likely that toxic concentrations of caf-
feine can be achieved from over-consumption of caffeinated beverages alone.
Introduction
Caffeine is a relatively innocuous drug, but to paraphrase a state-
ment made by Paracelsus (1492–1541) ~500 years ago, “Solely the
dose determines that a thing is not a poison”(1). This implies that
overdosing with caffeine, like anything else, can lead to toxicity and
death. After drinking a caffeinated beverage, the pharmacologically
active drug is rapidly absorbed into the blood and easily passes the
blood–brain barrier to function as a mild stimulant of the central
nervous system (2,3).
The amounts of caffeine contained in coffee, tea, soft-drinks and
energy-drinks vary depending on the source and method of prepar-
ation as well as the volume of a typical serving. Most caffeinated
beverages contain between 50 and 100 mg caffeine, which seems to
be an average amount per drink (4). Caffeine is also available in
powder or tablet form without a doctor’s prescription and people
use the drug as an appetite suppressant, to help stay awake longer
(counteract fatigue), to boost energy and increase alertness by func-
tioning as a general pick-me-up (5). Caffeine is sold over-the- coun-
ter in combination with other substances, such as ephedrine,
theophylline or aspirin, and these preparations might contain
between 100 and 200 mg of caffeine per tablet.
Millions of people drink several cups of coffee or tea daily without
any ill effects, although after chronic consumption some susceptible
individuals run the risk of habituation and concomitant dependence on
caffeine (6,7). The popularity of mixing caffeine-rich energy-drinks
with alcohol has raised some concern, owing to a perceived enhanced
© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 167
toxicity (8,9). However, expert opinions and publications about the
health hazards of drinking energy-drinks alone or together with alco-
hol are divided (10,11).
Because of the popularity of caffeinated drinks in society one can
expect to find measurable concentrations of caffeine in blood from a
randomly selected person (12). To avoid reporting insignificant
(therapeutic) concentrations of caffeine in routine casework, most
forensic toxicology laboratories use a relatively high analytical cut-
off concentration, such as 5–10 mg/L to report positive results.
This article reports caffeine concentrations in postmortem blood
from 51 caffeine-related poisoning deaths when the analytical meth-
od used was gas chromatography (GC). The results are discussed in
relation to age and gender of the deceased, the role of co-ingested
drugs and the manner of death according to the medical examiner
reports.
Methods
Original publications and case reports of caffeine-related deaths
were identified from searching PUBMED and also by scanning indi-
vidual journals specializing in analytical toxicology, forensic sci-
ence, legal medicine and clinical toxicology. This search strategy
located 51 well-documented intoxication deaths where caffeine was
the main psychoactive substance in postmortem blood. The concen-
trations of caffeine and other drugs in blood, the age and gender of
the deceased and the manner of death (accident, suicide or undeter-
mined) were available for scrutiny.
Femoral blood was used for toxicological analysis in 25 caffeine-
related deaths and in 19 cases cardiac blood was taken for analysis. In
the remaining seven cases the source of blood was not mentioned in the
published article. In four caffeine-related deaths both central and per-
ipheral blood samples were available for forensic analysis (13).
Also reviewed were papers reporting the caffeine content of various
caffeinated drinks, including coffees, teas, soft-drinks and energy-
drinks (14–17). This was considered relevant to help interpret concen-
trations of caffeine in blood in the poisoning deaths. Likewise, studies
of the pharmacokinetics of caffeine were reviewed to document
relevant kinetic parameters, such as plasma elimination half-life and
volume of distribution.
Some of the articles contained information from a single caffeine-
related poisoning death whereas others included 2–4 victims (18–23).
By far the largest case series, which comprised 20 caffeine intoxication
deaths, came from Sweden (24). Fatalities were also reported from
other countries, such as Japan (25), USA (13,26), Germany (27)and
Italy (28).
Results
Caffeine content in drinks
Caffeinated beverages are ubiquitous in society and millions of people
drink coffee, tea, soft-drinks and energy-drinks daily (29). The caffeine
contained in a large selection of such drinks was determined after
liquid–liquid extraction and use of capillary GC with a nitrogen–
phosphorous (N–P) detector (14–17). These concentrations of caffeine
are summarized in Table I. The GC method with N–P detector is well-
established in analytical toxicology and with slight modifications was
also used to determine caffeine in forensic blood samples (30).
The caffeine content of energy-drinks ranged from 0 to 77 mg/
240 mL per serving, whereas 360 mL of carbonated sodas contained
0–48 mg of caffeine (17). Other beverages, such as ice-tea and various
commercially available brewed coffees contained 3–106 mg caffeine
per 210 mL or 480 mL servings (16). Another study reported that
10 types of energy drink (240mL volumes) contained between 65 and
126 mg caffeine (30). Coffee advertised and sold as decaffeinated did
contain small amounts of caffeine, such as 18 mg/serving (15). This
compares with 58–258 mg/serving in caffeinated coffees from differ-
ent manufacturers and commercial outlets (16). Depending on the
method of preparation, a regular size serving of coffee might contain
~100 mg caffeine on the average.
Pharmacokinetics of caffeine
After drinking a caffeinated beverage, the caffeine they contain is rap-
idly absorbed from the stomach and intestines and the peak concen-
trations in blood or plasma are reached 30–90 min post-dosing (2).
The clinical pharmacokinetics of caffeine (1,3,7-trimethylxanthine) in
adults was dose-dependent and after large doses zero-order kinetics
occur, because the metabolizing enzymes are saturated with substrate
(31). In several human dosing studies, the systemic bioavailability of
caffeine was close to 100% indicating that first-pass metabolism is
negligible (31–33). Caffeine is extensively metabolized and only ~3%
of the dose is excreted unchanged in the urine (34).
After absorption into the blood, caffeine distributes into the total
body water compartment and the volume of distribution is within the
range 0.6–0.7 L/kg. The plasma elimination half-life of caffeine in adults
ranges from 3 to 7 h, although clearance rates are slower in neonates,
owing to late development of certain hepatic enzymes. Caffeine under-
goes N-demethylation by the action of hepatic cytochrome P4501A2
(CYP1A2) to give three primary metabolites, paraxanthine, theobro-
mine and theophylline. The CYP1A2 enzyme exhibits polymorphism,
which makes it likely that genetic factors might account for some of the
observed inter-individual variations in plasma pharmacokinetic profiles
and elimination half-life of caffeine (35,36). Furthermore, clearance of
caffeine might be slower in people with hepatic dysfunction.
Caffeine easily crosses the blood–brain barrier and acts as antag-
onist at receptor sites for the neurotransmitter adenosine (37).
Overdosing with caffeine causes excitement, agitation and people
experience tachycardia, heart palpitations and often require emer-
gency hospital treatment (38,39).
Caffeine-related deaths
The autopsy findings in caffeine-related deaths are non-specific and
acute toxicity is mostly ascribed to adverse cardiovascular events,
Table I. Caffeine content of various commercially available
caffeinated beverages determined after solvent extraction and GC
analysis with N–P detector (14–17)
Caffeinated beverage Caffeine content in volume
of typical servings
a
Various energy-drinks 0–141 mg
Carbonated sodas 0–48 mg
Other soft-drinks 3–106 mg
Coca Cola
b
41–48 mg
Specialty coffees 58–259 mg
Decaffeinated coffee 0–14 mg
Teas (white, green or black) 14–61 mg
a
Typical servings are 480 mL for coffees, 240mL for teas and 240–360mL
for energy-drinks and sodas.
b
Based on 480 mL serv ings purchased from 9 different outlets.
168 Jones
including cardiac arrhythmias and development of ventricular fibril-
lations (24,40). Elderly and frail people might be more susceptible
to the toxic effects of overdosing with caffeine than younger more
healthy individuals. High doses of caffeine are likely to cause sei-
zures and may need emergency medical treatment (39).
The available clinical and forensic toxicology literature contain
well-documented reports of caffeine-related poisoning deaths, mostly in
suicide attempts (41). Caffeine tablets are available in most nations as
an over-the-counter mild stimulant or pick-me-up. After four deaths
were reported in Sweden, the regulatory authorities issued warnings
and the number of tablets that could be purchased at one time was
restricted, although a follow-up study showed that overdosing with caf-
feine still continued (42). A detailed clinical course and the life-saving
treatment was presented for a 21-year-old female who attempted sui-
cide by swallowing 100 caffeine tablets, but she had second thoughts
and called emergency medical services (24).
All the articles reviewed used GC methods of analysis and infor-
mation was available about the victims age and gender, the manner
of death according to medical examiner report and the concentra-
tion of caffeine in postmortem blood (13,19,20,26,28). When the
victims were admitted to hospital for treatment, the typical signs
and symptoms reported were agitation, excitement, rapid and erratic
heat rhythm, respiratory distress, convulsions and entering a coma-
tose state before cessation of breathing (39).
Demographics of victims
Table II presents age and gender of the deceased in relation to the
concentrations of caffeine in postmortem blood. Most victims were
female (61%), although there was no significant difference in mean
age in relation to gender (t=0.811, P=0.421). Neither did the
mean (median) concentration of caffeine in blood depend on gender
♂=183 ±118 mg/L (162 mg/L) and ♀=190 ±82 mg/L (182 mg/L).
The median values were not significantly different according to non-
parametric Mann–Whitney U-test (z=1.187, P=0.235).
Figure 1shows a lack of correlation (R
2
coefficient of determin-
ation =0.026) between victims age and the concentration of caffeine
in postmortem blood. In this case series of 51 deaths the age of the
victims ranged from 18 to 84 years and 6 (12%) were above the age
of 60 years. Whether some natural disease, such as compromised
cardiovascular and/or respiratory function, might have been a con-
tributing factor in their deaths is not known. However, the mean
blood–caffeine concentration in people over 60 years was 160 mg/L
compared with a mean of 191 mg/L for those under 60 years.
Caffeine in central and peripheral blood
In 25 of the caffeine-related deaths, the drug was determined in fem-
oral blood whereas in 19 cases cardiac blood was collected for toxi-
cological analysis. In the remaining seven cases, the source of the
autopsy blood was not specified in the published articles. One study
analyzed caffeine in both cardiac and femoral blood and the results
were 47 vs 49 mg/L, 180 vs 220 mg/L, 80 vs 74 mg/L and 300 vs
320 mg/L, respectively, which shows fairly close agreement and
speaks against an appreciable postmortem redistribution (PMR) of
caffeine (13). The plasma/blood distribution ratios of caffeine are
also close to unity (43).
Manner of death
Table III presents manner of death in relation to the victim’s age and
gender and concentration of caffeine in postmortem blood. Mean
age of the victims was not significantly different for accidental, sui-
cide and undetermined manners of death (F=0.856, P=0.431).
The median concentrations of caffeine in blood was lowest for
undetermined manner of death (113 mg/L) and this differed signifi-
cantly from deaths classified as accidental (183 mg/L) and suicide
(185 mg/L), according to a non-parametric Kruskal–Wallis test (P=
0.023). Most of the caffeine-related deaths (N=26 or 51%) were
reported as being the result of a suicide attempt.
Table II. Concentrations of caffeine determined in postmortem
blood in poisoning deaths in relation to age and gender of the
deceased
Gender N(%) Age (years)
Mean ±SD
Blood–caffeine, mg/L
Mean ±SD (median) range
Males 20 (39) 42 ±17.2 183 ±118 (162) 47–567
Females 31 (61)
a
37 ±18.3
b
190 ±82 (182) 33–400
c
Both sexes 51 (100) 39 ±17.8 187 ±96 (180) 33–567
a
No significant difference in proportion of males to females; chi-squared =
2.31, P=0.128.
b
No significant difference in mean age of men and women by Student’s
t-test (t=0.811, P=0.42).
c
No significant gender difference in median concentration of caffeine in
blood by non-parametric Mann–Whitney U-test (z=1.187, P=0.235).
Figure 1. Lack of correlation between the concentrations of caffeine in post-
mortem blood and age of the deceased in 51 poisoning deaths.
Table III. Concentrations of caffeine in postmortem blood in relation
to manner of death according to medical examiner reports when the
cause of death was considered drug overdose (poisoning)
Manner of
death
N(%) Gender
M/F
Age (years)
mean ±SD
Blood–caffeine, mg/L
Mean ±SD
(median) range
Suicide 26 (51) 9/17 38 ±21.2 203 ±78 (185) 80–400
Undetermined 17 (33) 6/11 43 ±12.5 137 ±73 (113) 33–300
a
Accidental 8 (16) 5/3 34 ±15.3
b
240 ±147 (183) 134–567
All deaths 51 (100) 20/31 39 ±17.8 187 ±96 (180) 33–567
a
Median blood–caffeine concentration was significantly lower for undeter-
mined manner of death compared with accidental death and suicide, accord-
ing to non-parametric Kruskal–Wallis test, P=0.023.
b
No differences between mean age in relation to manner of death by one-
way ANOVA (F=0.856, P=0.431).
169Review of Caffeine-Related Fatalities
Co-ingested drugs
In the 51 poisoning deaths reviewed here, caffeine was the predom-
inant psychoactive substance identified in autopsy blood samples.
However, many of the victims had also used other drugs, such as
ethanol, paracetamol (acetaminophen), acetylsalicylic acid, ephe-
drine, antidepressants and/or antipsychotics. However, the concen-
trations of these other substances were mostly in the therapeutic
range, which suggests that they were incidental findings (44). Some
over-the-counter medicines contain caffeine in combination with an
analgesic or antipyretic drug, which explains the presence of these
substances in autopsy blood samples.
In a case series of caffeine intoxication deaths (N=20), caffeine
was the only drug identified in five cases at a mean concentration of
188 mg/L (24). This compares with a mean of 158 mg/L in 15 cases
when other drugs, in addition to caffeine, were identified in autopsy
blood. Ethanol was present in five cases at concentrations ranging
from 0.02 to 0.17 g%. In other victims, salicylic acid, acetamino-
phen and/or ephedrine were identified in blood samples, and these
substances were probably combined with caffeine in a pharmaceut-
ical product. Other drugs used by the victims of caffeine poisoning
included antidepressants (e.g., citalopram/escitalopram), sleep-aids
(zolpidem or zopiclone), antipsychotics (mirtazapine, olanzapine)
and benzodiazepines (oxazepam or flunitrazepam).
Concentrations of caffeine in postmortem blood
Figure 2presents a relative frequency distribution of caffeine con-
centrations in blood in 51 poisoning deaths. The distribution is
slightly skewed to the right as is often observed for drugs encountered
in overdose deaths. The mean (±SD), median and lowest and highest
concentrations of caffeine in postmortem blood were 187 ±96 , 180,
and 33–567 mg/L, respectively.
Figure 3is a cumulative frequency distribution plot, which
makes it easier to visualize the percentage of cases above certain
threshold concentrations of caffeine in blood. The median value
(50%) is indicated on the plot (180 mg/L) and the 10th and 90th
percentile concentrations were 84 and 314 mg/L, respectively.
Discussion and Conclusion
Musgrave et al. (45) recently published a paper entitled “Caffeine
toxicity in forensic practice: possible effects and under-appreciated
sources”although their review did not provide much information
about the blood concentrations of caffeine in poisoning deaths. The
present article presents descriptive statistics for the concentrations of
caffeine in 51 such deaths when caffeine was taken as tablets or in
powder form, although there might have been minor contributions
from drinking caffeinated beverages before death.
In a review of caffeine-related deaths in Tokyo between 2008 and
2013 when concentrations in blood were above 15 mg/L (N=22
cases) most victims were female (59%) aged between 20 and 49 years
(N=14) and 64–73% of the deceased had a history of some psychi-
atric disorder, mainly depression (25). The manner of death was certi-
fied as undetermined in 11 cases, accidental in 7 cases and suicide in 2
cases. In 16 deaths attributed to caffeine intoxication, the mean con-
centration in cardiac blood was 179mg/L, which compared with a
mean of 39mg/L when death was from other causes (N=6cases).The
mean concentration of caffeine in cardiac blood from the Japanese
study of 179mg/L is in good agreement with a mean of 187 mg/L in
the present compilation of 51 caffeine intoxication deaths.
In a listing of the drugs identified in blood in ~25,000 forensic aut-
opsies in Sweden representing all causes of death, we found that caffeine
was in 19th position in terms of prevalence (46). The use of a high ana-
lytical cut-off concentration of 10 mg/L ensures that cases with caffeine
present in blood from drinking caffeinated beverages are not included.
The mean, (median) and upper 97.5th percentile concentration of caffeine
in femoral blood were 22 mg/L, (14 mg/L) and 155 mg/L, respectively (N
=268 cases). This makes it clear that some of the deaths represent over-
dosing and intoxication from caffeine toxicity.
A retrospective study of 22,125 forensic autopsies reported in
Finland found mean, median and upper 97.5th percentile concentra-
tions of caffeine of 4, 3 and 13 mg/L, respectively (47). These concen-
trations are much lower than those form Sweden, but this Finnish
Laboratory used an analytical cut-off concentration of 1–3 mg/L.
The results therefore reflect blood–caffeine concentrations resulting
from normal consumption of caffeinated beverages. Taking a median
concentration of caffeine from the Finnish study as 3 mg/L, when this
is compared with a median of 180 mg/L in the 51 intoxication deaths
reported here, one arrives at a therapeutic index for caffeine in
humans of 60 (180/3 =60).
Various compilations of therapeutic, toxic and fatal concentra-
tions of drugs are available in the literature and these are useful to
Figure 2. Relative frequency distribution of caffeine concentrations in aut-
opsy blood from 51 victims of poisoning (overdose) deaths.
Figure 3. Cumulative frequency distribution of the concentrations of caffeine
in autopsy blood from 51 poisoning (overdose) deaths.
170 Jones
consider when drug overdose deaths are investigated (48). In one
such compilation, a caffeine concentration in blood below 10 mg/L
was considered harmless (49). Concentrations in blood between 15
and 20 mg/L were considered elevated, but still not toxic or a danger
to health, whereas levels between 80 and 180 mg/L were associated
with caffeine-related fatalities (49). Another compilation of caffeine-
related deaths reported that a concentration >100 mg/L in blood
should be interpreted as a poisoning or intoxication death (50).
The median concentrations of caffeine in 51 caffeine poisoning
deaths were 180 mg/L, and the 10th and 90th percentile concentra-
tions were 84 and 314 mg/L, respectively (Figure 3). Victims with a
relatively low concentration of caffeine in blood might have survived
for several hours or received hospital treatment, including hemodi-
alysis. During the survival time, the concentrations of caffeine in
blood decrease through metabolism (t
1/2
=3–7 h). Furthermore, the
co-ingestion of other drugs might have enhanced the toxicity of
caffeine, although for the 51 deaths reviewed here caffeine was the
predominant psychoactive substance in blood. Another factor to
consider is the presence of any natural disease, such as cardiovascu-
lar and respiratory problems in the elderly. These conditions might
make elderly individuals more susceptible to caffeine toxicity,
although the mean concentration in blood from people over 60
years (N=6) was 160 mg/L compared with a mean of 191 mg/L for
those younger than 60 years (N=45).
The propensity of caffeine to redistribute between blood and tis-
sue compartments after death has not been extensively studied by
direct comparison of central and peripheral blood concentrations.
The four cases reported in this paper do not support a significant
PMR (13). Caffeine distributes into the total body water compart-
ment and has a volume of distribution close to 0.70 L/kg on average
(31), so PMR is not expected to represent a serious problem for
interpreting blood concentrations of this drug.
In a 2012 review, Han et al. (43) reported a central-to-peripheral
distribution ratio of 1.1:1 (N=1) for caffeine. In a report from
Canada, Dalpe-Scott et al. (51) reported a mean heart/femoral blood
concentration ratio of 1.2:1 (range 1.0–1.4) in three cases. The con-
centrations of caffeine in femoral blood when bodies were admitted
to the mortuary (median 4.1 mg/L) were slightly higher than when
an autopsy was performed 59 h later (median 3.6 mg/L). This
decrease in concentration was statistically significant although
these caffeine concentrations are very low and not at all in the toxic
range (52).
Although it is generally considered controversial to convert a
postmortem drug concentration into the amount of substance in the
body at the time of death, especially for drugs with a propensity for
PMR, an exception might be made for caffeine until more informa-
tion becomes available. For a person with body weight of 70 kg and
180 mg/L caffeine in blood, a simple calculation shows that there
are 8.8 g caffeine absorbed and distributed in all body fluids and tis-
sues (0.180 g/L ×0.7 L/kg ×70 kg). If one caffeine tablet contains
100 mg then a 70 kg person would need to swallow ~88 tablets to
account for a postmortem blood concentration of 180 mg/L. This
large number of tablets is supported by the death of a 21-year-old-
woman who reported taking 100 caffeine tablets (10 g) in a suicide
attempt, but then had second thoughts and called the emergency ser-
vices (24). The woman died after 10 days of intensive care treat-
ment, including hemodialysis.
The manner of death whether accident, suicide or undetermined
was ascertained by medical examiner and/or forensic pathologists
who did an autopsy and after considering all available information
in the case. However, there may well be differences in how the
manner of death is certified in different countries and also between
medical examiner offices in the same country (53). This difference is
particularly evident when deciding between accidental as opposed to
undetermined manner of death, whereas suicide is more unequivo-
cal, for example, if a farewell note is discovered or the deceased suf-
fered from depression or had attempted suicide on a previous
occasion (54).
In conclusion, this review of the literature identified 51 caffeine-
related poisoning deaths with a mean concentration in blood (±SD)
of 187 ±96 mg/L (median 180 mg/L) and 10th and 90th percentile
concentrations of 84 and 314 mg/L, respectively. Most of the vic-
tims were females (61%) and the manner of death was suicide in
51% of cases. The average age of the deceased was 39 ±17.8 years
(range 18–84 years), although there was no correlation between
blood–caffeine concentration and victim’s age.
Funding
There was no external funding applied for nor received to prepare
this manuscript and the author does not consider he has any con-
flicts of interest to declare if this article is published in an inter-
national scientific journal.
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