Journal of Archaeological Science 54 (2015) 162e167

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Journal of Archaeological Science

journal homepage: http://www.elsevier.com/locate/jas

A medieval case of digitalis poisoning: the sudden death of Cangrande

della Scala, lord of verona (1291e1329)
Gino Fornaciari a, b, Valentina Giuffra a, b, *, Federica Bortolotti c, Rossella Gottardo c,
Silvia Marvelli d, Marco Marchesini e, Silvia Marinozzi f, Antonio Fornaciari a, b,
Giorgio Brocco g, Franco Tagliaro c
a
Division of Paleopathology, Department of Translational Research on New Technologies in Medicine and Surgery, University of Pisa, Via Roma 57,
56126 Pisa, Italy
b
Center for Anthropological, Paleopathological and Historical Studies of the Sardinian and Mediterranean Populations, Department of Biomedical Sciences,
University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
c
Unit of Forensic Medicine, Department of Public Health and Community Medicine, University of Verona, P.le L.A. Scuro 10, 37134 Verona, Italy
d
Palynological Laboratory, Archaeoenvironmental Laboratory, C.A.A. Giorgio Nicoli, Via Marzocchi 17, 40017 San Giovanni in Persiceto, Italy
e
Superintendence to Archaeological Properties of Emilia-Romagna, Via Belle Arti, 52, 40126 Bologna, Italy
f
Section of History of Medicine, Department of Experimental Medicine, University of Rome “La Sapienza”, Viale dell'Universita 34a, 00185 Rome, Italy
g
Section of Biological Chemistry, Department of Life and Reproduction Sciences, University of Verona, Strada Le grazie 8, 37134 Verona, Italy

a r t i c l e i n f o a b s t r a c t

Article history: The natural mummy of Cangrande della Scala was exhumed from its tomb in the church of Santa Maria
Received 11 April 2014 Antiqua in Verona and was submitted to a multidisciplinary study, that included archaeological, palae-
Received in revised form opathological, palynological, toxicological and historical investigation. The body of Cangrande, still
24 September 2014
wearing his precious clothes, was in a good state of preservation. Palynological analyses demonstrated
Accepted 6 December 2014
the presence of pollen grains of Digitalis sp./foxglove in the rectum content, along with Matricaria
Available online 13 December 2014
chamomilla/chamomille and Morus nigra/black mulberry. Toxicological analyses showed toxic concen-
trations of digoxin and digitoxin, two Digitalis glycosides, in the liver and faeces samples. Both palyno-
Keywords:
Middle Ages
logical and toxicological data suggest an intoxication through the oral administration of an infusion or
Natural mummy decoction of leaves and flowers of Digitalis.
Foxglove Cangrande died on July 22 1329, four day after his triumphal entrance in the city of Treviso. The sudden
Digitalis death was preceded by vomit and diarrhoea with fever that, according to written documents, he had
Palynology contracted a few days before by “drinking from a polluted spring”. The gastrointestinal symptoms
Toxicology manifested by Cangrande in his last hours of life are compatible with the early phase of Digitalis
Digoxin intoxication and the hypothesis of poisoning is mentioned by some local historical sources. The palae-
Digitoxin
opathological analyses confirm a Digitalis poisoning. The most likely hypothesis on the causes of death is
that of a deliberate administration of a lethal amount of Digitalis. Although several cases of poisoning
through the use of organic substances are known from historical sources, no other direct evidences are
documented in the palaeopathological literature.
© 2014 Elsevier Ltd. All rights reserved.

1. Introduction

Cangrande della Scala (1291e1329) is the most celebrated

* Corresponding author. Division of Paleopathology, Department of Translational
Research on New Technologies in Medicine and Surgery, University of Pisa, Via
Roma 57, 56126 Pisa, Italy. Tel.: þ39 050992894; fax: þ39 050992706.
E-mail addresses: gino.fornaciari@med.unipi.it (G. Fornaciari), v.giuffra@
med.unipi.it (V. Giuffra), federica.bortolotti@univr.it (F. Bortolotti), rossella.
gottardo@univr.it (R. Gottardo), smarvelli@caa.it (S. Marvelli), marco.
marchesini@beniculturali.it (M. Marchesini), silvia.marinozzi@uniroma1.it
(S. Marinozzi), a.fornaciari@tele2.it (A. Fornaciari), giorgio.brocco@
ospedaleuniverona.it (G. Brocco), franco.tagliaro@univr.it (F. Tagliaro).
member of the Scaligeri dynasty, which ruled Verona from 1277 to
1387 (Varanini, 1988; Spangenberg, 1993).
Leading patron of the poet Dante Alighieri, who composed a
letter (Epistola XIII) in honour of his host in Verona (Branca, 1907),
Cangrande was a great warrior and an important autocrat of his
time. After the death of his brother Alboino he became the sole
ruler of Verona in 1311, at the age of twenty. Cangrande was
regarded as the leader of the Ghibelline party in Northern Italy,

http://dx.doi.org/10.1016/j.jas.2014.12.005
0305-4403/© 2014 Elsevier Ltd. All rights reserved.
 G. Fornaciari et al. / Journal of Archaeological Science 54 (2015) 162e167
bringing the city of Vicenza under his control (1314). After several
years of intermittent and brutal conflicts he took possession of
Padua (1328) and Treviso (1329).
On 18 July 1329 the entrance of Cangrande into the city of Tre-
viso represented the crowning achievement of his long struggle to
submit the entire region of Veneto (Northern Italy). However, his
triumph was marred by the fact that he had become seriously ill as
a result of vomit and diarrhoea, which he had contracted a few days
before by “drinking from a polluted spring”, according to contem-
porary accounts (Varanini, 2004). Cangrande died on the morning
of July 22.
The body of Cangrande was temporarily housed in the church of
Santa Maria Antiqua in Verona, but it then appears to have been
moved twice, first to a marble tomb in the churchyard and secondly
to the monumental marble tomb over the church entrance, above
which there is an equestrian statue of Cangrande in tournament
armour (Fornaciari, 2004; Napione, 2006) (Fig. 1).
In February 2004 the tomb of Cangrande was opened to allow a
multidisciplinary study of the corpse, which included archaeolog-
ical, palaeopathological, palynological, toxicological and historical
investigation. The natural mummy, still wearing its precious
clothes, appeared in good state of preservation (Napione, 2006).
The aim of this paper was to investigate the causes of Can-
grande's death, taking also into consideration that rumours of
poisoning are reported by traditional chronicles (Varanini, 2004).
2. Materials and methods
2.1. Palaeopathological study
The mummy of Cangrande (Fig. 2) was submitted to autopsy
(Fig. 3a), performed through a circular opening of the abdomen,
from the sternum to the pubis, which allowed to reach the
Fig. 1. The equestrian statue of Cangrande (Castelvecchio Museum, Verona).
163
abdominal and thoracic cavities (Fornaciari, 2004, 2006). The
viscera appeared to be collapsed on the posterior wall and were
identified according to their topographical position. Macroscopic,
radiological and histological studies were performed. The latter
included rehydration with Sandison solution (Sandison, 1955),
routine paraffin-embedding and standard haematoxylin-eosin and
Van Gieson's staining procedures.
2.2. Palynological analysis
Samples for palynological analyses were taken from two inter-
nal regions of Cangrande's mummy, the left hemi-abdomen (colon)
and the rectum content (faeces). The analyses were carried out
applying an already tested analytical approach (Giuffra et al., 2011).
The method includes the following phases: addition of a tablet of
Lycopodium spores re-suspended in HC1 10% for the calculation of
pollen concentration (¼number of pollen grains/gram); treatment
with acetic acid to dehydrate the preparation; Erdtman acetolysis;
addition of 40% of HF without pre-heating for 24 h; washings in
distilled water; addition of ethanol; desiccation in thermostatic
oven; preparation of glycerine jelly-fixed slides. The observation of
the samples was performed at 1000 light microscope magnifi-
cation (ocular 10 and objective 100) with the help of keys,
atlases and a reference pollen collection. In particular, the identi-
fication of the Digitalis pollen was obtained by using a manual
(Moore et al., 1991), whereas that of Digitalis cf. purpurea was based
on the comparison with the laboratory collection of the authors.
The pollen terminology is based on Berglund and Ralska-
Jasiewiczowa (1986). The botanic terminology follows Pignatti
(1982).
2.3. Toxicological analysis
Toxicological analyses were performed on different samples
taken from the mummy of Cangrande to detect any traces of poi-
sons or toxic substances or to find evidences of any possible
pharmacological treatments, which could explain his rapid death.
In particular, the toxicological analyses were carried out on a
sample of hair (100 mg) from the head vertex, two samples of
rectum content (approximately 5 g each), and two liver samples
(approximately 5 g each), which have been collected during the
autopsy.
The extracts of the hair sample, of one faeces sample, and of one
liver sample underwent screening toxicological analyses by using
CE and HPLC-MS methods.
The CE analyses were performed on a P/ACE-MDQ capillary
electropherograph equipped with a diode-array detector operating
at 214 nm (Beckman Coulter, Fullerton, CA, USA). Separations were
carried out at 25  C in an uncoated fused-silica capillary (Composite
Metal Service Worcester, UK), with an internal diameter of 50 mm
and a total length of 60 cm, using a buffer composed of 100 mM
phosphate (pH 2.38) (Hudson et al., 1995).
The HPLC-MS analyses were performed on a 1100 HPLC coupled
with a MSD-ion trap mass spectrometer, model SL (Agilent Tech-
nologies, Palo Alto, CA) using a Zorbax Eclipse XDB (2.1  150 mm,
5 mm particle size, Agilent Technologies) with gradient elution from
5% to 95% of solvent B lasting 20 min (solvent A: formic acid 0.1%;
solvent B: methanol). The spray voltage was set at 4 kV and the
skimmer at 40 V. For peak identification, the ion trap mass spec-
trometer was set to perform MS2 on the molecular ion of the
selected compounds, using helium as collision gas.
The results of screening analyses were confirmed by using a
1100 HPLC coupled with a quadrupole Time of Flight Mass Spec-
trometry (Q-TOF MS) Ultima (Waters MS Technologies, Manchester,
UK). The separation was performed using a Synergi Hydro column
164 G. Fornaciari et al. / Journal of Archaeological Science 54 (2015) 162e167

Fig. 2. The natural mummy of Cangrande at exhumation in 2004.

Fig. 3. The abdomen at the moment autopsy (a); the well-preserved liver (b).

150  4.6 mm (Phenomenex, Torrance, CA) with gradient elution

from 5% to 95% of solvent B lasting 50 min (solvent A: ammonium
formate 10 mmol, pH 5; solvent B: acetonitrile). Electrospray
ionization, in positive mode, was used. The HPLC flow was split
(1:5) between the mass spectrometer and the waste. Analytes were
identified on the basis of charged molecular ions, mass accuracy,
and their collision-induced dissociation fragmentation.
A liver sample and a faeces sample underwent immunochemical
analyses in order to determine digoxin and digitoxin. The samples
were pulverised and rehydrated with distilled water in a proportion
of 50:50. After 24 h, the samples were submitted to ultrasonication
(35 kHz) for 3 min and then centrifuged for 15 min a 1500  g. The
determination of digoxin was carried out by using different antisera
[Digoxin IMMULITE® (Diagnostic Products Corporation, Los
Angeles, USA); Digoxin Tina-quant® (Roche Diagnostic GmbH,
Mannheim, Germania); Digoxin Assay Emit® 2000 (Syva Company,
Dade Behring Inc., Cupertino, USA)] to minimize the risk of errors
caused by cross-reactions. The determination of digitoxin was
carried by using IMMULITE/IMMULITE® 1000 (Diagnostic Products
Corporation, Los Angeles, USA).

3. Results

3.1. Palaeopathological study

The palaeopathological study revealed that Cangrande suffered

Fig. 4. CT of the toraco-abdominal cavities, with the liver well recognizable (*) and
faeces in the rectal ampulla (arrows).
from mild osteoarthritis of the column, elbows and hips, with a
meniscus calcification of the knees, probably related to the strong
intense physical activity of the Prince. The liver was well recog-
nizable, showing a typical anatomic shape, with a transversal
diameter of 30 cm, both at macroscopic examination (Fig. 3b) and at
Computed Tomography (CT) (Fig. 4). The presence of faeces in the
rectal ampulla was observed (Fig. 4). Histology demonstrated small
atheromatous plaques on the luminal surface of the aorta, as well as
a picture of severe anthracosis, irregular emphysema and fibro-
 G. Fornaciari et al. / Journal of Archaeological Science 54 (2015) 162e167
hyaline nodular formations, probably attesting the results of
tuberculosis, at the level of lungs.
3.2. Palynological analysis
Palynological analysis includes 4 taxa: 3 of Spermatophyta (1
trees/shrubs and 2 herbs) and 1 taxon of Pteridophyta. In the left
hemi-abdomen (524 pollen grains/g) 2 taxa, Matricaria chamomilla
(chamomile) (83.3%) and Morus nigra (black mulberry) (16.7%)
were found. In the rectum (863 pollen grains/g) large amounts of
Matricaria chamomilla (88.9%) (Fig. 5a) and few pollen grains of
Digitalis (foxglove) were identified (11.1%) (Fig. 5b).
It was difficult to determine whether the pollens belonged to
Digitalis purpurea L. or Digitalis lanata Ehrh. Indeed, the scarce
amount of plant material found in the mummy prevented the use of
DNA barcoding, a genetic technique already used for ancient plant
remains to individuate without doubts the taxonomic identity of
pollen elements (Gismondi et al., 2012, 2013). However, the
morphological characteristics suggested that the pollens could
belong to Digitalis cf. purpurea. This plant was largely cultivated in
the past centuries with medicinal purposes. Nowadays it is wide-
spread as ornamental plant, while several wild populations are
known in woody glades and mountain pastures of the Alps and the
spontaneous plant is present in Corse and Sardinia (Pignatti, 1982).
3.3. Toxicological analysis
The capillary electrophoretic and HPLC-MS analyses evidenced
in the hair traces of harman and santonin, which are compounds
contained in Passiflora sp. L. (passionflower) and Artemisia sp. L.
(wormwood), respectively. Santonin was also found in the faeces
and in the liver samples. Both Passiflora and Artemisia are histori-
cally well-known medical plants, which were used for their phar-
macological properties. The presence of these substances in the
hair could be explained by the administration of an external
treatment or by the oral administration of a concoction. The latter
possibility would be supported by the identification of santonin in
the faeces and in the liver. Nevertheless, no one of these com-
pounds shows a considerable toxicity.
Immunochemical analyses of faeces and liver samples showed
significant quantities of compounds immunoreactively similar to
digoxin and digitoxin, which are two glycosides of Digitalis. The two
Fig. 5. Pollen of Matricaria chamomilla L. (28,3 micron) (a) and of Digitalis (24,5 micron) (b) found in the rectum content.
165
Table 1
Concentration values of digoxin and digitoxin in the liver and feces of Cangrande.
Digoxin-DPC Digoxin Roche Digoxin Syva Digitoxin-DPC
Liver (ng/g) 14.0 5.6 16.8 62.4
Rectal feces 15.6 7.2 11.2 41.6
(ng/g)
glycosides were identified in toxic concentrations, in order of tens
of ng/g, as showed in Table 1.
4. Discussion
Several palynological studies, which were carried out over the
past decades on the graves of important historical personages, have
helped obtain valuable information on the intake of vegetable food
and beverages consumed before the death, ingestion of toxic or
poisonous substances, use of particular aromatic substances in
funerary rites, origin of the clothes found in the burial, and vege-
tation of a particular range (Paganelli, 1981; Bertolani Marchetti
and Mariotti Lippi, 1993; Scannerini, 1997; Paganelli, 2003;
Marchesini and Marvelli, 2006; Piombino Mascali et al., 2013).
In the case of Cangrande, palynological spectra, although at low
concentration values (102e103 pollen grains/gram), showed the
intake of vegetal components by the Prince in the last moments of
his life. In particular, they showed the ingestion of foxglove leaves
and flowers.
Some papers are published on the significance of low taxa
pollen spectra and low values of entomophilous plants in archae-
obotanical (Mercuri, 2008) and paleoforensic cases (Piombino
Mascali et al., 2013). In the case of Cangrande the prevalent
ingestion of foxglove leaves instead of flowers could explain the
low concentration values of pollen grains.
Toxicological analyses have shown the presence of two active
principles of Digitalis, digoxin and digitoxin, in liver and faeces
samples. The concentrations of Digitalis glycosides determined in
these experiments after the rehydration of samples in a ratio of 50/
50 are in the toxic range (Baselt, 2008). However, taking into ac-
count a reasonably high loss of the compounds during the seven
centuries elapsed since Cangrande's death, it is possible to infer
that the digoxin and digitoxin concentrations measured in the
tissues of the Prince at death time were well above the lethal
concentrations.
166 G. Fornaciari et al. / Journal of Archaeological Science 54 (2015) 162e167
An integrated evaluation of the experimental data provided by
palynological and toxicological study clearly suggests an intoxica-
tion through the oral administration of an infusion or decoction of
leaves and flowers of Digitalis. Autopsy could not reveal any alter-
ation referable to Digitalis intoxication because acute poisoning
does not leave traces at macroscopic level.
Digitalis poisoning is characterized by gastrointestinal symp-
toms including nausea, vomiting, diarrhoea, abdominal pain; cen-
tral nervous manifestations, in particular somnolence,
hallucinations, delirium and severe headache; effects on the heart
like abnormal rhythms, the most serious of which is ventricular
tachycardia, that can cause heart block (Bayer, 1991).
The gastrointestinal symptoms manifested by Cangrande in his
last hours of life and described by historical sources are compatible
with the early phase of Digitalis intoxication. The symptomatology
of Cangrande includes vomiting and diarrhoea with acute pain
(“fluxus ventris”, “fluxu obiit”, “corporeus fluxus stomachique dolor
acutus”); sometimes there is reference to fever (“fluxum et febrem
continuam ob laborem exercitus”) (Varanini, 2004).
It is difficult to ascertain whether the Digitalis fatal intoxication
of Cangrande was an intentional murder or a terrible mistake. The
therapeutic properties of foxgloves were discovered in the second
half of 18th century (Doyle, 2009), but the toxic effects of the plant
must have been known much earlier. Unfortunately there is a gap in
the documentary sources, since references to foxglove as a poison
were not found before Renaissance times. Even if foxglove grew
over the most part of Europe, it was never mentioned by Dio-
scorides, Theophrastus or other ancient writers.
One of the first historical source on the Digitalis is a manuscript
copy of the Herbarium Apuleii Platonici, written at Bury St. Edmunds
around 1120, where the English word foxglove appears along with
the names of other plants prescribed to compose topical ointments
for the treatment of wounds (Groves and Bisset, 1991). According to
the medical and botanical literature from Roman to Modern age, all
these plants are described and defined as poisonous, and employed
as analgesics, hypnotics and narcotics only in small doses (Mattioli,
1563; Paulus Aegineta, 1846; De Renzi, 1853; Galenus, 1964e5;
Plinius Secundus, 1969e1974; Theophrastus, 1980; McVaugh,
2008).
The sudden disappearance of a powerful and relatively young
man probably favoured the circulation of rumours about this
death. Although some diseases are occasionally mentioned, such
as the imprecise illnesses of 1315 and 1325, Cangrande was
healthy, despite the great physical efforts during the military
campaigns of the last twenty years of his life. The hypothesis of
poisoning is mentioned by some local historical sources, even if
the documents are not anterior to the second half of the 14th
century. A vernacular Venetian chronicle written soon after 1354
and the chronicler Galeazzo Gatari in the last part of the 14th
century report that Cangrande was poisoned (Varanini, 2004). The
Veronese notary Boninsegna da Mizzole, author of a local chron-
icle between 14th and 15th century, and the notary and historian
Torello Saraina in the 15th century claimed that the poison had
been hidden in a fruit (Varanini, 2004). On the other hand,
poisoning was a diffused practice in the European Middle Ages
(Collard, 2003).
Some details about poisoning modalities are reported in the
15th century by a Treviso chronicler (Anonimo foscariniano), who
claims that the physician accused of poisoning had been impris-
oned and hung after the confession. This dubitative and late version
seems to be confirmed by a more authoritative source, the jurist
and chronicler Guglielmo Cortusi, who was ambassador in Verona
in 1328 and close to the environment of Alberto II della Scala
(1306e1352), co-ruler of Verona after the death of Cangrande
together with his brother Mastino II (1308e1351); according to
Cortusi, who is silent about the causes of Cangrande's death, his
physician died on the gallows (Varanini, 2004).
Considering that the therapeutic properties of Digitalis were
recognized only in Modern times (Fuchs, 1549), in the case of
Cangrande an accidental ingestion of a vegetal mixture including
flowers and leaves of Digitalis should not be excluded; glycoside
ingestion probably occurred as a result of an erroneous identifica-
tion of leaves, not always easy to distinguish from those of other
edible plants, as occurs also today. Accidental poisonings conse-
quent to ingestion of herbal concoctions containing foxglove leaves
are reported in modern clinical literature (Dickstein and Kunkel,
1980; Bain, 1985; Maffe  et al., 2009; Lin et al., 2010; Mitchell,
2010; Castello et al., 2012).
But the most likely hypothesis is that of a deliberate adminis-
tration of a lethal amount of Digitalis; the poison may have been
masked in a decoction containing chamomile and black mulberry,
prepared for some indisposition of Cangrande. Although several
cases of poisoning through the use of organic substances are known
from historical sources (Smith, 1952), no other direct evidences are
documented in palaeopathological literature.
5. Conclusions
The multidisciplinary study performed on the natural mummy
of Cangrande della Scala supports the hypothesis that Cangrande
was victim of digitalis poisoning. Palynological analyses demon-
strated the presence of foxglove as pollen grains in the rectum
content and toxicological analyses confirmed the presence of two
active principles of Digitalis, digoxin and digitoxin, present in toxic
concentration in the liver and faeces. Although it is not possible to
rule out totally an accidental intoxication, the most likely hypoth-
esis is that of a deliberate administration of a lethal amount of
Digitalis. It is more problematic to detect the instigator of the
murder. The principal suspects are the neighbouring states, the
Republic of Venice or Ducate of Milan, worried about the new
regional power of Cangrande and Verona; at the death of Can-
grande also his ambitious nephew Mastino, who became ruler of
Verona in association with his brother Alberto, cannot be totally
excluded as instigator.
The case of Cangrande represents the unique direct evidence of
poisoning through the use of organic substances in the palae-
opathological literature.
Acknowledgements
We would to thank Prof. Daniela Fausti (University of Siena),
Alain Touwaide (Smithsonian Institution e National Museum of
Natural History of Washington) and Andrea Ubrizsy Savoia (Uni-
versity of Rome “La Sapienza”) for providing important information
about the historical research to identify foxglove in ancient medical
and naturalist literature. Moreover, we would thank Dr. Silvia
Martinucci (GSK Verona) for the confirmation analysis of santonin
and harman, and Prof. Giacomo Gortenuti (University of Verona) for
the imaging study.
A special thank to Dr. Paola Marini, Director of the Castelvecchio
Museum, Verona.
This work was supported by a grant from the ARPA Foundation
(www.fondazionearpa.it).
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