ArticlePDF AvailableLiterature Review

Review of Caffeine-Related Fatalities along with Postmortem Blood Concentrations in 51 Poisoning Deaths

Authors:

Abstract and Figures

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 (161 mg/L) was not significantly different from that of females (182 mg/L), z = 1.18, P = 0.235. There was no correlation between the age of the deceased and the concentration of caffeine in postmortem blood (R2 = 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 caffeine can be achieved from over-consumption of caffeinated beverages alone.
Content may be subject to copyright.
Journal of Analytical Toxicology, 2017;41:167172
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 1884 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 signicant (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 33567 mg/L, respectively. The median concentration of caffeine in
males (161mg/L) was not signicantly 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 classied as suicide in 51% of cases
(median bloodcaffeine 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 identied 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 (14921541) ~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
bloodbrain 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 doctors 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 nd measurable concentrations of caffeine in blood from a
randomly selected person (12). To avoid reporting insignicant
(therapeutic) concentrations of caffeine in routine casework, most
forensic toxicology laboratories use a relatively high analytical cut-
off concentration, such as 510 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 identied 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 (1417). 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 24 victims (1823).
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
liquidliquid extraction and use of capillary GC with a nitrogen
phosphorous (NP) detector (1417). These concentrations of caffeine
are summarized in Table I. The GC method with NP detector is well-
established in analytical toxicology and with slight modications 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
048 mg of caffeine (17). Other beverages, such as ice-tea and various
commercially available brewed coffees contained 3106 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 58258 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 3090 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 rst-pass metabolism is
negligible (3133). 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 0.60.7 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 proles
and elimination half-life of caffeine (35,36). Furthermore, clearance of
caffeine might be slower in people with hepatic dysfunction.
Caffeine easily crosses the bloodbrain 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 ndings in caffeine-related deaths are non-specic 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 NP detector (1417)
Caffeinated beverage Caffeine content in volume
of typical servings
a
Various energy-drinks 0141 mg
Carbonated sodas 048 mg
Other soft-drinks 3106 mg
Coca Cola
b
4148 mg
Specialty coffees 58259 mg
Decaffeinated coffee 014 mg
Teas (white, green or black) 1461 mg
a
Typical servings are 480 mL for coffees, 240mL for teas and 240360mL
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 bril-
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 signicant 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 signicantly different according to non-
parametric MannWhitney U-test (z=1.187, P=0.235).
Figure 1shows a lack of correlation (R
2
coefcient 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
bloodcaffeine 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 specied 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 victims age and
gender and concentration of caffeine in postmortem blood. Mean
age of the victims was not signicantly 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 signi-
cantly from deaths classied as accidental (183 mg/L) and suicide
(185 mg/L), according to a non-parametric KruskalWallis 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
Bloodcaffeine, mg/L
Mean ±SD (median) range
Males 20 (39) 42 ±17.2 183 ±118 (162) 47567
Females 31 (61)
a
37 ±18.3
b
190 ±82 (182) 33400
c
Both sexes 51 (100) 39 ±17.8 187 ±96 (180) 33567
a
No signicant difference in proportion of males to females; chi-squared =
2.31, P=0.128.
b
No signicant difference in mean age of men and women by Students
t-test (t=0.811, P=0.42).
c
No signicant gender difference in median concentration of caffeine in
blood by non-parametric MannWhitney 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
Bloodcaffeine, mg/L
Mean ±SD
(median) range
Suicide 26 (51) 9/17 38 ±21.2 203 ±78 (185) 80400
Undetermined 17 (33) 6/11 43 ±12.5 137 ±73 (113) 33300
a
Accidental 8 (16) 5/3 34 ±15.3
b
240 ±147 (183) 134567
All deaths 51 (100) 20/31 39 ±17.8 187 ±96 (180) 33567
a
Median bloodcaffeine concentration was signicantly lower for undeter-
mined manner of death compared with accidental death and suicide, accord-
ing to non-parametric KruskalWallis 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 identied 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 ndings (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 identied in ve 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 identied in autopsy
blood. Ethanol was present in ve cases at concentrations ranging
from 0.02 to 0.17 g%. In other victims, salicylic acid, acetamino-
phen and/or ephedrine were identied 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 unitrazepam).
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 33567 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
sourcesalthough 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 6473% of the deceased had a history of some psychi-
atric disorder, mainly depression (25). The manner of death was certi-
ed 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 identied 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 13 mg/L.
The results therefore reect bloodcaffeine 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
=37 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 signicant
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 1.01.4) 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 signicant 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 uids 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 certied in different countries and also between
medical examiner ofces 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 identied 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 1884 years), although there was no correlation between
bloodcaffeine concentration and victims 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-
icts of interest to declare if this article is published in an inter-
national scientic journal.
References
1. Deichmann, W.B., Henschler, D., Holmstedt, B., Keil, G. (1986) What is
there that is not poison? A study of the Third Defense by Paracelsus.
Archives of Toxicology,58, 207213.
2. Axelrod, J., Reichenthal, J. (1953) The fate of caffeine in man and a meth-
od for its estimation in biological material. The Journal of Pharmacology
and Experimental Therapeutics,107, 519523.
3. Benowitz, N.L. (1990) Clinical pharmacology of caffeine. Annual Review
of Medicine,41, 277288.
4. Mitchell, D.C., Knight, C.A., Hockenberry, J., Teplansky, R., Hartman,
T.J. (2014) Beverage caffeine intakes in the U.S. Food and Chemical
Toxicology,63, 136142.
5. Beauchamp, G.A., Johnson, A.R., Crouch, B.I., Valento, M., Horowitz,
B.Z., Hendrickson, R.G. (2016) A retrospective study of clinical effects of
powdered caffeine exposures reported to three US poison control centers.
Journal of Medical Toxicology,12, 295300.
6. Nutt, D., King, L.A., Saulsbury, W., Blakemore, C. (2007) Development
of a rational scale to assess the harm of drugs of potential misuse. Lancet,
369, 10471053.
7. Nehlig, A. (1999) Are we dependent upon coffee and caffeine? A review
on human and animal data. Neuroscience and Biobehavioral Reviews,
23, 563576.
8. Alford, C., Hamilton-Morris, J., Verster, J.C. (2012) The effects of energy
drink in combination with alcohol on performance and subjective aware-
ness. Psychopharmacology,222, 519532.
9. Benson, S., Verster, J.C., Alford, C., Scholey, A. (2014) Effects of mixing
alcohol with caffeinated beverages on subjective intoxication: a system-
atic review and meta-analysis. Neuroscience and Biobehavioral Reviews,
47,1621.
10. Alford, C., Scholey, A., Verster, J.C. (2015) Energy drinks mixed with
alcohol: are there any risks? Nutrition Reviews,73, 796798.
11. Verster, J.C., Aufricht, C., Alford, C. (2012) Energy drinks mixed with
alcohol: misconceptions, myths, and facts. International Journal of
General Medicine,5, 187198.
12. Blanchard, J., Sawers, S.J. (1983) Comparative pharmacokinetics of caf-
feine in young and elderly men. Journal of Pharmacokinetics and
Biopharmaceutics,11, 109126.
13. Banerjee, P., Ali, Z., Levine, B., Fowler, D.R. (2014) Fatal caffeine intoxi-
cation: a series of eight cases from 1999 to 2009. Journal of Forensic
Sciences,59, 865868.
171Review of Caffeine-Related Fatalities
14. Chin, J.M., Merves, M.L., Goldberger, B.A., Sampson-Cone, A., Cone, E.J.
(2008) Caffeine content of brewed teas. Journal of Analytical Toxicology,
32,702704.
15. McCusker, R.R., Fuehrlein, B., Goldberger, B.A., Gold, M.S., Cone, E.J.
(2006) Caffeine content of decaffeinated coffee. Journal of Analytical
Toxicology,30, 611613.
16. McCusker, R.R., Goldberger, B.A., Cone, E.J. (2003) Caffeine content of
specialty coffees. Journal of Analytical Toxicology,27, 520522.
17. McCusker, R.R., Goldberger, B.A., Cone, E.J. (2006) Caffeine content of
energy drinks, carbonated sodas, and other beverages. Journal of
Analytical Toxicology,30, 112114.
18. Hanzlick, R., Gowitt, G.T., Wall, W. (1986) Deaths due to caffeine in
look-alike drugs.Journal of Analytical Toxicology,10, 126.
19. Jabbar, S.B., Hanly, M.G. (2013) Fatal caffeine overdose: a case report
and review of literature. The American Journal of Forensic Medicine and
Pathology,34, 321324.
20. Kerrigan, S., Lindsey, T. (2005) Fatal caffeine overdose: two case reports.
Forensic Science International,153,6769.
21. McGee, M.B. (1980) Caffeine poisoning in a 19-year-old female. Journal
of Forensic Sciences,25,2932.
22. Winek, C.L., Wahba, W., Williams, K., Blenko, J., Janssen, J. (1985)
Caffeine fatality: a case report. Forensic Science international,29,207211.
23. Yamamoto, T., Yoshizawa, K., Kubo, S., Emoto, Y., Hara, K., Waters, B.
et al. (2015) Autopsy report for a caffeine intoxication case and review of
the current literature. Journal of Toxicologic Pathology,28,3336.
24. Thelander, G., Jonsson, A.K., Personne, M., Forsberg, G.S., Lundqvist,
K.M., Ahlner, J. (2010) Caffeine fatalitiesdo sales restrictions prevent
intentional intoxications? Clinical Toxicology,48, 354358.
25.Suzuki,H.,Tanifuji,T.,Abe,N.,Maeda,M.,Kato,Y.,Shibata,M.et al.
(2014) Characteristics of caffeine intoxication-related death in Tokyo, Japan,
between 2008 and 2013. Nihon Arukoru Yakubutsu Igakkai zasshi =
Japanese Journal of Alcohol Studies & Drug Dependence,49, 270277.
26. Garriott, J.C., Simmons, L.M., Poklis, A., Mackell, M.A. (1985) Five
cases of fatal overdose from caffeine-containing look-alikedrugs.
Journal of Analytical Toxicology,9, 141143.
27. Riesselmann, B., Rosenbaum, F., Roscher, S., Schneider, V. (1999) Fatal
caffeine intoxication. Forensic Science International,103, S49S52.
28. Bonsignore, A., Sblano, S., Pozzi, F., Ventura, F., DellErba, A., Palmiere, C.
(2014) A case of suicide by ingestion of caffeine. Forensic Science, Medicine,
and Pathology,10,448451.
29. Barone, J.J., Roberts, H.R. (1996) Caffeine consumption. Food and
Chemical Toxicology,34, 119129.
30. Ayala, J., Simons, K., Kerrigan, S. (2009) Quantitative determination of
caffeine and alcohol in energy drinks and the potential to produce positive
transdermal alcohol concentrations in human subjects. Journal of
Analytical Toxicology,33,2733.
31. Kaplan, G.B., Greenblatt, D.J., Ehrenberg, B.L., Goddard, J.E., Cotreau,
M.M., Harmatz, J.S. et al. (1997) Dose-dependent pharmacokinetics and
psychomotor effects of caffeine in humans. Journal of Clinical
Pharmacology,37, 693703.
32. White, J.R. Jr., Padowski, J.M., Zhong, Y., Chen, G., Luo, S., Lazarus, P.
et al. (2016) Pharmacokinetic analysis and comparison of caffeine admi-
nistered rapidly or slowly in coffee chilled or hot versus chilled energy
drink in healthy young adults. Clinical Toxicology,54, 308312.
33. Cheng, W.S., Murphy, T.L., Smith, M.T., Cooksley, W.G., Halliday,
J.W., Powell, L.W. (1990) Dose-dependent pharmacokinetics of caffeine
in humans: relevance as a test of quantitative liver function. Clinical
Pharmacology and Therapeutics,47, 516524.
34. Blanchard, J., Sawers, S.J. (1983) The absolute bioavailability of caffeine
in man. European Journal of Clinical Pharmacology,24,9398.
35. Perera, V., Gross, A.S., McLachlan, A.J. (2012) Measurement of CYP1A2
activity: a focus on caffeine as a probe. Current Drug Metabolism,13,
667678.
36. Perera, V., Gross, A.S., Xu, H., McLachlan, A.J. (2011) Pharmacokinetics
of caffeine in plasma and saliva, and the inuence of caffeine abstinence
on CYP1A2 metrics. The Journal of Pharmacy and Pharmacology,63,
11611168.
37. Chen, J.F., Eltzschig, H.K., Fredholm, B.B. (2013) Adenosine receptors as
drug targetswhat are the challenges? Nature Reviews Drug Discovery,
12, 265286.
38. Glade, M.J. (2010) CaffeineNot just a stimulant. Nutrition,26,
932938.
39. Rudolph, T., Knudsen, K. (2010) A case of fatal caffeine poisoning. Acta
Anaesthesiologica Scandinavica,54, 521523.
40. Pelchovitz, D.J., Goldberger, J.J. (2011) Caffeine and cardiac arrhythmias: a
review of the evidence. The American Journal of Medicine,124,284289.
41. Silva, A.C., de Oliveira Ribeiro, N.P., de Mello Schier, A.R., Pereira, V.M.,
Vilarim, M.M., Pessoa, T.M. et al. (2014) Caffeine and suicide: a system-
atic review. CNS & Neurological Disorders Drug Targets,13,937944.
42. Holmgren, P., Norden-Pettersson, L., Ahlner, J. (2004) Caffeine fatalities
four case reports. Forensic Science International,139,7173.
43. Baselt, R.C. Disposition of Toxic Drugs and Chemicals in Man, 9th edi-
tion. Biomedical Publications: Seal Beach, CA, 2011.
44. Patel, G. (2012) Postmortem drug levels: innocent bystander or guilty as
charged. Journal of Pharmacy Practice,25,3740.
45. Musgrave, I.F., Farrington, R.L., Hoban, C., Byard, R.W. (2016) Caffeine
toxicity in forensic practice: possible effects and under-appreciated sources.
Forensic Science, Medicine, and Pathology,12, 299303.
46. Jones, A.W., Holmgren, A. (2009) Concentration distributions of the
drugs most frequently identied in post-mortem femoral blood represent-
ing all causes of death. Medicine, Science, and the Law,49, 257273.
47. Launiainen, T., Ojanpera, I. (2014) Drug concentrations in post-mortem
femoral blood compared with therapeutic concentrations in plasma. Drug
Testing and Analysis,6, 308316.
48. Molina, D.K. Handbook of Forensic Toxicology for Medical Examiners.
CRC Press: Boca Raton, 2010.
49. Schulz, M., Schmoldt, A. (2003) Therapeutic and toxic blood concentra-
tions of more than 800 drugs and other xenobiotics. Die Pharmazie,58,
447474.
50. Winek, C.L., Wahba, W.W., Winek, C.L. Jr., Balzer, T.W. (2001) Drug
and chemical blood-level data 2001. Forensic Science International,122,
107123.
51. Dalpe-Scott, M., Degouffe, M., Garbutt, D., Drost, M. (1995) A com-
parison of drug concentrations in postmortem cardiac and peripheral
blood in 320 cases. Canadian Journal Forensic Science Society,28,
113121.
52. Gerostamoulos, D., Beyer, J., Staikos, V., Tayler, P., Woodford, N.,
Drummer, O.H. (2012) The effect of the postmortem interval on the
redistribution of drugs: a comparison of mortuary admission and autopsy
blood specimens. Forensic Science, Medicine, and Pathology,8, 373379.
53. Warner, M., Paulozzi, L.J., Nolte, K.B., Davis, G.G., Nelson, L.S. (2013)
State variation in certifying manner of death and drugs involved in drug
intoxication deaths. Acad Forensic Pathol,3, 231237.
54. Advenier, A.S., Guillard, N., Alvarez, J.C., Martrille, L., Lorin de la
Grandmaison, G. (2016) Undetermined manner of death: an autopsy ser-
ies. Journal of Forensic Sciences,61, S154S158.
172 Jones
... Unregulated or loosely regulated supplementation, along with an unguided acquisition of the supplement, opens the way to overdose and potentially fatal outcomes [4]. ...
... Additional investigations may show hyperglycemia, hypokalemia, rhabdomyolysis, renal failure, and hyperlactacidemia. Toxic concentrations of caffeine, enough to provoke severe outcomes, are not likely to be achieved only with caffeinated beverages, with most fatal case reports reporting the use of powdered or tablet forms of supplementation [4]. Moderate consumption, at a total daily dose of 400 mg, is usually not associated with adverse effects [5]. ...
... To achieve toxic drug levels, a patient would need to drink more than 100 cups of coffee in a relatively short time span. As such, overdose on caffeinated beverages seems unlikely [4]. On the other hand, easily acquired highly concentrated caffeine, powder or capsule, is almost always involved in severely symptomatic patients, and the tendency seems to be rising. ...
Article
Full-text available
Caffeine is an integral part of beverages, food, and medications. Severe intoxication of caffeine is rare, and reports are even scarcer. However, over-the-counter, unregulated sale of performance-enhancing compounds, such as caffeine, turns high-dose consumption into a real concern. Severe intoxication may be fatal, usually by malignant cardiac arrhythmia. We report a case of a 23-year-old university student who accidentally consumed about 100 times the amount present in an expresso of anhydrous caffeine.
... There is no agreement upon the lethal dose of caffeine, however serum concentrations above 80 mg/L are considered lethal, these levels are typically seen after ingestions exceeding 5g. A recent review showed a mean caffeine concentration of 187 ± 96 mg/L with ranges between 33-567 mg/L in patients who died from caffeine intoxication [21]. Nevertheless, there might be individuals who can have serious toxicity and lethality below this range [22,23]. ...
... Lethal concentration 80 mg/L most common mechanisms are rhythm disturbances, with ventricular fibrillation the most frequently described. Myocardial infarction caused by coronary artery vasospasm has also been proposed as one of the causes [21,24]. We did an extensive literature search and review and to date there were 21 well-documented reports of caffeine overdose in adults treated with dialysis techniques. ...
Article
Full-text available
Caffeine, chemically 1,3,7-trimethylxanthine, is the most widely consumed central nervous system stimulant in the world with pleiotropic effects on the cardiovascular, pulmonary, and renal systems. The advent of over the counter (OTC) caffeine formulations has opened the window for potential toxicity, either by inadvertent or intentional overdosing. We present the case of a patient who attempted suicide by caffeine overdose treated with emergent haemodialysis and a review of the literature.
... The side effects of caffeine usually occur following the intake of high dosages and include anxiety, tachycardia, restlessness, mood changes, insomnia, psychomotor agitation, changes in the flow of thought and speech. Toxic effects appear for dosages of 1.2 g or higher (over 20 cups), while the dose deemed lethal is believed to be over 10 g (75-100 cups of coffee consumed in a short time) [2]. Coffee has a variable caffeine content depending on how it is prepared. ...
... Indeed, coffee consumption was correlated with a reduction in the risk of major cardiovascular events with a greater benefit in subjects consuming between 3 and 5 cups of coffee per day [7]. Regarding the relationship between coffee consumption and arrhythmias related to hypertension, numerous studies have found that coffee consumption is inversely associated with the onset of atrial fibrillation and tachyarrhythmias in general, especially supraventricular ones [2]. ...
Article
Full-text available
A growing number of epidemiological studies have reported the beneficial effects of habitual coffee consumption on incident cardiovascular disease (CVD), and mortality. However, the effects of coffee on arterial hypertension are still objects of active discussion mainly because of the debated effects of caffeine on blood pressure and cardiovascular system. In particular, the negative impact of caffeine would involve the whole cardiovascular system and could be responsible for an excess in the relative risk of new onset of hypertension and a worsening of blood pressure control. Recent evidence has been published excluding a significant effect of coffee consumption on hypertension development and blood pressure control in treated and untreated hypertensive supporting a protective role for the antioxidant components of coffee that may counteract the claimed negative effect of caffeine. The presence and amount of caffeine and cardio-protective chemical constituents of coffee is largely dependent on the type, production, and method of preparation and this can partially explain the divergent opinions on the effects of coffee intake on blood pressure and cardiovascular system. In addition, some genetic aspect of caffeine metabolism can contribute to the heterogeneity of published evidence while the most recent cardiovascular guidelines largely endorse coffee consumption in hypertension and CV disease. The purpose of this short review is to briefly summarise some of the recent information available in the literature on coffee and blood pressure. • Key points • According to the considerable amount of observational evidence we can suggest that: • While acute coffee administration in non-habitual users may induce a blood pressure rise, habitual coffee consumption in medium-high dosages (from 3 to 5 cups/day), has neutral or even beneficial impact on blood pressure values and the new onset of hypertension. • • The same intake significantly reduces the incidence of cardiovascular disease, as well as all-cause mortality. • • The consumption of coffee is compatible with a correct and balanced lifestyle and should therefore not be discouraged in subjects with hypertension and cardiovascular diseases.
... Blood caffeine level below 10 μg mL −1 was considered harmless. Caffeine concentration between 15 and 20 μg mL −1 in blood was considered elevated, but still not toxic or a danger to health, whereas levels between 80 and 180 μg mL −1 were associated with caffeine-related fatalities (Jones 2017). Therefore simple, sensitive, and reliable methods are necessary for preconcentration and extraction of CF and TP from pharmaceutical preparations, biological samples, and food products. ...
Article
A rapid and simple ultrasound-assisted surfactant-enhanced emulsification microextraction procedure with chloroform-decanoic acid (87:13 w/w) as the extractant mixture has been improved for the simultaneous preconcentration of caffeine and theophylline before their determination using high-performance liquid chromatography. The use of ultrasonic radiation and surfactant can enhance the dispersion of extraction solvent into an aqueous phase and simplify the emulsification process. The proposed method is an environmentally friendly pretreatment method because of its low solvent consumption. Various parameters influencing the efficiency of the method including pH, buffer, extraction solvent, extraction time, and interfering ions were studied. The linear calibration curves were obtained in the ranges of 0.5–150 and 2–150 ng mL−1 with limits of detection of 0.22 and 0.15 ng mL−1 for caffeine and theophylline, respectively. The proposed procedure was successfully utilized for the determination of caffeine and theophylline in cocoa powder and human plasma samples. Based on the obtained results, it can be concluded that the proposed method is potentially applicable as an efficient method for preconcentration and determination of caffeine and theophylline in real samples such as food and biological media.
... Blood concentration of caffeine in the range 80 -100 mg/mL, corresponding with approximate dose 10 grams for an adult is considered lethal and blood concentration of caffeine around 15 mg/L can initiate seizures and cardiac arrhythmias [77]. Average blood caffeine level 187±96 mg/L was proved in a study on 51 victims of fatal poisoning by caffeine in accidents or suicides [78]. Sensitivity to the side effects of caffeine can be higher in like children, adolescents, or the elderly than in the adult population [79][80][81][82]. ...
Article
Caffeine, a simple purine alkaloid with the proper chemical name 1,3,7-trimethylpurine-2,6-dione, is an abundant compound contained in beverages like coffee, food and drugs. It interacts with various pathways of which antagonism of adenosine receptors is the most significant but the other physiological pathways can be influenced by caffeine as well. Interaction with glutamate and dopamine neurotransmission pathways, competition with other substrates on cytochrome P450, non-competitive inhibition of acetylcholinesterase, blocking of nicotinic acetylcholine receptor and competitive inhibition of cyclic nucleotide phosphodiesterase can be mentioned. Because of caffeine availability as a part of foods, beverages and drugs, it has practical relevance even if the effect is weak. Intake of coffee containing edibles for a long period or even for a substantial part of life makes caffeine´s impact significant. Low acute and chronic toxicity of caffeine is another important specification. The discoveries from the last few years point to the fact that caffeine would interfere with the progression of some age-related neurodegenerative disorders like Alzheimer and Parkinson diseases and dementia with Lewy bodies. In this review article, the recent findings about caffeine´s impact on neurodegenerative diseases are presented and important facts about the caffeine effect including the substantial discoveries are described.
... Caffeine inhibits the ability of peripheral tissues to regulate their blood supply (hence oxygen delivery) during pressure-flow autoregulation [23], reactive hyperemia (24), and active or exercise hyperemia (unpublished ongoing investigation). Under extreme conditions the compound is capable of causing sudden cardiac death by limiting coronary circulation and causing ventricular tachycardia and/or fibrillation [25]. More experimental investigation is needed on the physiology and pathophysiology of caffeine, its analogs (e.g. ...
Article
Caffeine is the drug of choice for adults of the world. It is commonly found in the favorite beverages they consume such as coffee, energy drinks, soft drinks and tea. The caffeine molecule is a decorative sculpture that helps visitors identify the recently-constructed Chemistry and Chemical Biology Building on the Busch Campus of Rutgers University, Piscataway, New Jersey.
Article
Caffeine content is a crucial attribute of coffee. Its concentration and thus maximum cups of Coffea arabica from Africa, Asia, Central America, and South America from different altitudes of growing areas, altitude, and process using different post-harvest processing (dry, wet, and pulped natural). Our results suggest that geographical origin might affect the alkaloid concentration in C. arabica. The caffeine concentration pattern in green samples was as follows: Central America > South America > Asia > Africa. Altitude affected the concentrations, lowlands > midlands > highlands, however, not significantly. Given caffeine is thermostable, the medium roasting process did not affect the concentration of caffeine directly, but a small increase was observed. Scientific opinion on the safety of habitual caffeine consumption of up to 400 mg per day does not raise safety concerns for non-pregnant adults. A cup (7 g coffee in 120 mL of water) was used for recalculation. Results suggest that mostly highlands and midlands coffee from Africa reached levels of caffeine that might be consumed in more than 5.5 cups a day.
Article
Protein phosphorylation is a critical way that cells respond to external signals and environmental stresses. However, the patterns of cellular response to chemicals at different times were largely unknown. Here, we used quantitative phosphoproteomics to analyze the cellular response of kinases and signaling pathways, as well as pattern change of phosphorylated substrates in HepG2 cells that were exposed to caffeine and coumarin for 10 min and 24 h. Comparing the 10 min and 24 h groups, 33 kinases were co-responded and 32 signaling pathways were co-enriched in caffeine treated samples, while 48 kinases and 34 signaling pathways were co-identified in coumarin treated samples. Instead, the percentage of co-identified phosphorylated substrates only accounted for 4.31% and 9.57% between 10 min and 24 h in caffeine and coumarin treated samples, respectively. The results showed that specific chemical exposure led to a bunch of the same kinases and signaling pathways changed in HepG2 cells, while the phosphorylated substrates were different. In addition, it was found that insulin signaling pathway was significantly enriched by both the caffeine and coumarin treatment. The pattern changes in phosphorylation of protein substrates, kinases and signaling pathways with varied chemicals and different time course shed light on the potential mechanism of cellular responses to endless chemical stimulation.
Article
Full-text available
Many dietary supplements may contain harmful ingredients or compounds. One of them is caffeine, a stimulant that has been utilized globally for centuries, primarily for its ability to improve mental alertness. This report described a case involving a young woman who most likely intentionally took an energy booster containing pure caffeine. Gross and microscopic examination showed extensive necrotic changes with esophageal perforation in the upper gastrointestinal tract. Harmful contents have moved to the posterior mediastinum and the left pleural cavity, causing injuries within them. Postmortem toxicological tests (gas chromatography with the mass detector—GC-MS) have shown the presence of lethal levels of caffeine in the blood (92.0 ug/mL). The remaining toxicological tests were negative.
Article
Full-text available
Caffeine is considered a very safe stimulant and is widely consumed in a variety of forms, from pure caffeine to beverages and foods. Typically, death is only seen when gram quantities of caffeine are consumed, usually in suicide attempts. Even in this scenario, death is rare. However, there are special populations that need to be considered in forensic presentations, who may be at greater risk. These include poor metabolizers, people with liver disease, and people with cardiac conditions, who can die as a result of caffeine intake at levels well below what is ordinarily considered toxic. Also, caffeine intake may be hidden. For example, herbal medicines with substantial caffeine content may not disclose these concentrations on their product label. The role of caffeine in medicolegal deaths is yet to be defined, however, herbal medicines and herbal weight loss supplements may represent an underappreciated source of caffeine in this context.
Article
Full-text available
Context: There is a paucity of data describing the impact of type of beverage (coffee versus energy drink), different rates of consumption and different temperature of beverages on the pharmacokinetic disposition of caffeine. Additionally, there is concern that inordinately high levels of caffeine may result from the rapid consumption of cold energy drinks. Objective: The objective of this study was to compare the pharmacokinetics of caffeine under various drink temperature, rate of consumption and vehicle (coffee versus energy drink) conditions. Materials: Five caffeine (dose = 160 mg) conditions were evaluated in an open-label, group-randomized, crossover fashion. After the administration of each caffeine dose, 10 serial plasma samples were harvested. Caffeine concentration was measured via liquid chromatography-mass spectrometry (LC-MS), and those concentrations were assessed by non-compartmental pharmacokinetic analysis. The calculated mean pharmacokinetic parameters were analyzed statistically by one-way repeated measures analysis of variance (RM ANOVA). If differences were found, each group was compared to the other by all pair-wise multiple comparison. Results: Twenty-four healthy subjects ranging in age from 18 to 30 completed the study. The mean caffeine concentration time profiles were similar with overlapping SDs at all measured time points. The ANOVA revealed significant differences in mean Cmax and Vd ss/F, but no pair-wise comparisons reached statistical significance. No other differences in pharmacokinetic parameters were found. Discussion: The results of this study are consistent with previous caffeine pharmacokinetic studies and suggest that while rate of consumption, temperature of beverage and vehicle (coffee versus energy drink) may be associated with slightly different pharmacokinetic parameters, the overall impact of these variables is small. Conclusion: This study suggests that caffeine absorption and exposure from coffee and energy drink is similar irrespective of beverage temperature or rate of consumption.
Article
Full-text available
Introduction Anhydrous caffeine, often sold on the Internet as a powdered caffeine product, is sold as “pure caffeine” to be used as an additive to beverages and has also been used as an ingredient in energy supplement products. Methods This is a retrospective multiple-poison center chart review of calls regarding powdered caffeine to poison centers covering Oregon, Alaska, Guam, Washington, and Utah between January 1, 2013 and June 30, 2015. Results There were 40 calls to three poison centers over 30 months for powdered caffeine exposure. The majority of patients were over age 19 (52.5 %; 21/40) and male (70 %; 28/40). Sixty percent (24/40) of the patients were symptomatic but only 10 % (4/40) required admission; 52.5 % (21/40) of the patient calls were for inadvertent overdose of powdered caffeine; one patient overdosed in a self-harm attempt. Discussion Powdered caffeine calls to three poison centers during a 30-month study period were rare, and severe caffeine toxicity due to exposure was found in few patients. The majority of symptoms were reported after an inadvertent powdered caffeine overdose. Conclusions An analysis of calls to three poison centers for powdered caffeine found that exposures were uncommon, but did result in toxicity, and highlighted that the lack of clear dosing instructions on product packaging may place patients at risk of inadvertent overdose.
Article
Full-text available
National statistics on drug intoxication deaths are based solely on data derived from death certificates. This study examines the variation in the manner of death classification by state, and the specificity of drugs involved in drug intoxication deaths by state and by type of death investigation system. The National Vital Statistics System Multiple Cause of Death mortality files (2008-2010) were analyzed. Drug intoxication deaths were those with ICD-10 Underlying Cause of Death of X40-X44 (unintentional), X60-X64 (suicide), X85 (homicide), or Y10-Y14 (undetermined intent). Among drug intoxication deaths, deaths involving non-specified drug(s) were those with Multiple Cause of Death (MCOD) of T50.9, and no MCOD in the range T36-T50.8. State death investigation systems were categorized as follows: centralized state medical examiner offices, county/district medical examiners, hybrid, and decentralized county coroners. In 2008-2010, there was an average of over 37,250 drug intoxication deaths per year in the U.S. The manner was undetermined for 8% for the U.S., ranging from 1% to 85% among the states. During 2008-2010, 75% of the drug intoxication deaths had at least one specific drug reported on the death certificate. States with centralized state medical examiner systems had a higher percent (92%) of drugs specified than did those with other systems. Across the U.S., there is variation in the percent of drug intoxication deaths classified as having undetermined manner of death and with specific drugs identified on death certificates. This variation has significant implications for public health surveillance and for prevention efforts.
Article
Full-text available
Caffeine (1,3,7-trimethylxanthine) is a popular mild central nervous system stimulant found in the leaves, seeds and fruits of various plants and in foodstuffs such as coffee, tea, and chocolate, among others. Caffeine is widely used and is not associated with severe side effects when consumed at relatively low doses. Although rarely observed, overdoses can occur. However, only a few fatal caffeine intoxication cases have been reported in the literature. Herein, we report the pathological examination results and information on caffeine concentrations in the blood, urine and main organs in a fatal caffeine intoxication case. Even though high caffeine concentrations were found in the systemic organs, no caffeine-related pathological changes were detected.
Article
A manner of death may be ruled undetermined by the forensic pathologist when there is insufficient information about the circumstances surrounding the death to make a ruling. The aim of our study was to retrospectively analyze a series of autopsy cases that were classified as undetermined manner of death after complete investigations. In all, 48 cases were examined. In 23 cases (48%), the cause of death was determined. The most frequent cause of death was toxic death (n = 11). More than one manner of death was deemed conceivable for most cases (n = 39). The most frequent and the most probable manner of death was accident (n = 37). Homicide was not excluded in about 23% of the cases. Our study showed that the manner of death may remain undetermined despite an established cause of death, and even when two or more conceivable causes of death are considered. Our study pointed out that undetermined manner of death covers a wide range of situations and that homicide may be underestimated. © 2015 American Academy of Forensic Sciences.
Article
Caffeine is widely available in beverages and over-the-counter products; however, in large doses, it can lead to lethal arrhythmia. This study aims to clarify the characteristics of caffeine intoxication-related deaths in Tokyo, Japan. Among the 4754 forensic autopsy cases between 2008 and 2013 in which a toxicological investigation was performed, cases in which the blood concentration of caffeine exceeded toxic levels (15 μg/ml) were selected (N = 22). We examined subjects' ages, medical histories, direct/underlying causes of death, and manner of death. We also assessed concurrent drug substance detection and identified the origin of the caffeine. More than 60% of the subjects were between the ages of 20 and 49 years (n = 14, 63.6%). Sixteen cases (72.7%) showed a history of psychiatric diseases such as depression and sleep disorders. The underlying cause of death for all cases except two was caffeine intoxication, and manner of death was classified as undetermined (n = 11), accidental (n = 7), suicide (n = 2), or others (n = 2). Toxicological analysis revealed the presence of ingredients common to analgesics/cold remedies in 12 cases (54.5%). The origin of the caffeine was identified in 11 cases (50.0%); the proportion of identification was significantly lower among the cases in which analgesic/cold remedy ingredients were not detected (20.0%). Caffeine intoxication-related deaths mainly occurred in young and middle-aged persons with common psychiatric diseases. Psychiatrists should take note of caffeine dependence while diagnosing common psychiatric symptoms. In half of the cases, the origin of the caffeine was unidentified; nevertheless, dietary sources or over-the-counter drugs containing caffeine were suspected. As it becomes easier to obtain caffeinated products, continuous monitoring of the number of deaths from caffeine intoxication, in addition to detailed investigations of the caffeine's origin, will be necessary.
Article
For many years it has become increasingly apparent from literature reports that the postmortem cardiac blood concentrations of certain drugs can be significantly different than those found in peripheral blood. The cardiac to peripheral ratio (C/P) of drug concentrations in postmortem blood samples was determined for 113 drugs representing toxicological findings in 320 cases. Theories postulated in current scientific literature to explain observed site dependence of drug concentration in postmortem blood are discussed in light of the findings. It is suggested that drug quantifications be done on both cardiac and peripheral blood and that the final interpretation of results be done as a team effort by all individuals involved in the death Investigation.