60

L
egend has it that Mithridates VI (d. 63 BCE), King of Pontus
on the Black Sea, made himself immune to poisons by
taking an antidote of his own devising. For the next 2000
years, an antidote called mithridatum or mithridatium
was included in materia medica and pharmacopoeia
throughout Europe. In Mithridatess day, poison and anti-
dote had somewhat different connotations than they do
today. A poison commonly referred to an extract of plants
containing alkaloids such as henbane (hyoscyamine), wolfs
bane (aconitine), or poison hemlock (coniine). Venoms of poi-
sonous animals were also included. Antidotes were sweet-
smelling lotions and potions believed to antagonize poisons.
A poison could also develop inside a person without expo-
sure to poisonous plants or animals. Thus, it was thought that
systemic poisons were present in illnesses and these could
be ameliorated by the same antidotes.
Early in the nineteenth century, the attitude toward alkaloids
changed; they became compounds of interest as drugs.
Morphine was isolated from opium and its structure deter-
mined, followed by other alkaloids, including a number of
atropine-related compounds. Until well into the twentieth
century, the study of pharmacology focused on alkaloids,
from d-tubocurarine to morphine, that acted on receptors in
the nervous system, and the old antidotes were forgotten or
dismissed. Recent studies on secondary metabolites in plants,
however, have opened the possibility of examining the ingre-
dients of the old antidotes for bioactivity.
History of Mithridatum
About 300 BCE, Theophrastus wrote in his treatise on odors
that a sweet-smelling mixture known as megalium could
relieve the inflammation caused by any wound. Megalium
contained five ingredients: A resin plus oil of balanos
[(Balanites aegyptiaca), an Egyptian shrub], cassia, cin-
namon, and myrrh (1). Centuries later, Plutarch described
a similar mixture, called Egyptian cyphi, with some addi-
tional ingredients, that was used as an incense by priests
in their rituals, as well as used as an unguent or potion (2).
In the first century BCE, Zopyrus, physician to King Ptolemy,
in Alexandria, wrote a letter to Mithridates in which he
described a remedy that included most of the ingredients in
megalium and cyphi (3). Mithridates created the remedy now
called mithridatum, possibly with the aid of his botanist-physi-
Reflections
Science in the cultural context
61
April 2006
Volume 6, Issue 2
cian, Crataeus, and the earliest known formulae for mithrida-
tum contain many of the ingredients suggested by Zopyrus
plus some additional odoriferous plants.
About 100 years after the death of Mithridates, Celsus wrote
down a formula for mithridatum (4) that included fifteen of
the twenty plants in Zopyruss formula. Celsus proposed
that the antidote was useful in serious conditions, such as
a fall from a height or for internal pains, and was neces-
sary against poisons in food or venomous bites. The recom-
mended dose was an amount the size of an almond, to be
taken daily. This mithridatum contained thirty-six ingredients,
thirty-four of which were from plants (Table 1). The other two
components were honey, for mixing the ingredients, and cas-
tor (musk from beaver glands). Various musks were commonly
used in perfumes and ointments to mask offensive odors, thus
enhancing the overall aroma. Both
non-plant ingredients were also
used in six different versions of mith-
ridatum reported by Galen (3).
In the second century CE, Galen,
physician to Marcus Aurelius, cre-
ated his own version and called
it theriac. In his treatise on
antidotes, Galen listed several ver-
sions: One by Aelius, used by Julius
Caesar; one by Andromachus,
physician to Nero; and one each
by Antipater, Nicostratus, and
Damocratis. Galen noted that the formula Zopyrus sent to
Mithridates was useful against deadly poisons and for dis-
orders of the stomach and bowels. He called the version
prepared by Nicostratus an incomparable antidote for all
internal indispositions of the body (3). These remedies were
carefully prepared. The amount of each ingredient by weight
was precisely stated. Recommendations for sequence of mix-
ing, such as which ingredients were best ground together,
were often included. Honey (and, occasionally, a little wine)
was added at the end to make a good confection. The dose
administered was expressed as volume relative to the size
of a bean or nut. The list of ingredients was varied accord-
ing to the physicians preference.
For example, the formulae given
by Celsus and Andromachus were
similar both in kinds of ingredients
and in the amounts of each to be
used. One of the main ingredients
in Celsuss formula was ginger
about 4.3% of the total weight of
the formula. The same ingredient
was one of the most plentiful by
weight in Andromachuss formula.
In Nicostratuss formula, however,
this ingredient made up only 1.8 %
of the total weight of seventy-eight
ingredients.
In the following centuries, other versions appeared (Figure
1). Some versions were called theriac, after Galens version,
and usually contained even more ingredients than mithri-
datum. The Antidotarium Nicolai, a book of antidotes pub-
lished in Salerno, Italy, in the mid twelfth century, contained
a theriac boasting sixty-one ingredients (5). The London
Pharmacopoeia of 1659 listed sixty-three ingredients in a
version of mithridatum. This version was recommended as a
general antidote for illnesses: If your body be not in health,
then take one dram or between one and two, according
to age and strength (6).
In the next century, the
number of ingredients in
mithridatum in the London
Pharmacopoeia had
dropped to forty-seven (7).
In the later versions of the
book, plants more acces-
sible in Europe were often
substituted for some of the
old plants from the Near
East and Africa.
Interest in mithridatum
gradually disappeared.
By the nineteenth century,
the version in the Italian
Pharmacopoeia contained
twenty-eight ingredients
Pharmacology of Mithridatum
Shepherds purse
Mithridates
Percent
(Relative to
Celsuss version)
Cyphi
(16)
Zopyrus
(20)
Celsus
(36)
Nicostratus
(78)
Antidotarium
Nicholai
(61)
London
Pharmacopoeia
(64)
London
Pharmacopoeia
(47)
Italian
Pharmacopoeia
(28)
100
75
50
25
0
400 200 0 200 1200 1600 1800 2000
BCE CE
Figure 1. Ingredients in versions of mithridatum as percent of Celsuss version. The total number of ingredients
is in parentheses with the name of the version. Note that the time line is broken in two places.
62
Reflections
Table 1. Plants Used in Mithradatum
Scientific Name Plant Family Common
Name
Part Used
a
Bioactive
Ingredient
Chemical
Category
Mechanism
b
Acacia arabica
Willd.
Fabaceae Acacia Gum from
branches (18)
Fisetin
c
flavonoid inhibits cytokine
expression (19)
Acorus calamus L. Acoraceae Sweet flag Root (20) Asarone phenylpropanoid antioxidant in vivo (21)
Athamanta
cretensis L.
Apiaceae Cretan
carrot
Seed (18) Imperatorin
d
furanocoumarin inhibits NFAT binding to
DNA (22)
Boswellia carterii
Birdw.
Burseraceae Frankin-
cense
Gum resin
(23)
Acetyl
11-keto-beta-
boswellic acid
triterpene inhibits leukotriene
synthesis (24)
Capsella bursa-pas-
toris (L.) Medik
Brassicaceae Shepherds
purse
Herb (25) Fumaric acid dicarboxylic acid protects against toxic
chemicals in vitro (25)
Centaurium
erythraea Raf.
Gentianaceae Lesser cen-
taury
Herb (26) Swertiamarin monoterpene antioxidant (26)
Cinnamomum cas-
sia Bl.
Lauraceae Cassia Bark, leaf (27) 2-Hydroxy cin-
namaldehyde
phenolic inhibits NF-B
activation (27)
Cinnamomum
zelanicum Bl.
Lauraceae Cinnamon Bark (28) Coniferyl alde-
hyde
e
, eugenol
phenylpropanoids antioxidants (28, 29)
Commiphora myrrha
(Nees) Engl.
Burseraceae Myrrh Gum resin
(20)
Furanodiene sesquiterpene inhibits lipopolysaccha-
rideinduced NO
production (30)
Commiphora opo-
balsmum (L.) Engl.
Burseraceae Balm of
Gilead
Gum resin
(31)
Extract protects against gastric
ulcers (31)
Crocus sativus L. Iridaceae Saffron Herb and
flower (32)
Crocin crocetin di-gentobi-
ose ester
ester and plant extract
are antioxidants (33)
Cyperus rotundus L. Cyperaceae Sweet rush Rhizome (34) Isocurcumenol sesquiterpene inhibits NO production
(30)
Cytinus hypocistis L. Rafflesiaceae Hypocistis Juice of herb
(35)
Gallic acid
f
phenolic acid antioxidant (36)
Elettaria cardamo-
mum (L.) Maton
Zingiberaceae Cardamom Seed capsule
(36)
Extract Extract inhibits platelet
aggregation and lipid
peroxidation (37)
Ferula assafoetida L. Apiaceae Assafoetida Gum (38) Ferulic acid
g
phenolic acid antioxidant (39)
Ferula gummosa
Boiss.
Apiaceae Galbanum Gum (40) Alpha and
beta-pinene
monoterpenes may act in dyspepsia
(40)
Ferula persica Willd. Apiaceae Sagapenum Gum (41) Extract
Hypericum
perforatum L.
Hyperiaceae St Johns
wort
Herb (42) Hyperforin phloroglucinol multiple effects on gene
expression (42)
Liquidambar
orientalis Mill.
Hamamelidaceae Storax Bark resin (18) Casuarinin ellagitannin antioxidant (43)
Nardostachys
jatamansi
(G.Don) DC.
Valerianaceae Indian nard Herb (44) Extract Extract protects against
lipid peroxidation (44)
Opopanax
chironium Koch.
Apiaceae Opopanax Gum resin
(45)
Imperatorin furanocoumarin antiplatelet aggregation
activity (46)

63
April 2006
Volume 6, Issue 2
Pharmacology of Mithridatum
and was recommended only for dyspepsia (8). Mithridatum
had failed as a remedy in many different conditions in which
it was tried, such as plague and epilepsy. The growing inter-
est in chemistry and the concern for specific remedies for
specific diseases also contributed to the decline of mithrida-
tum. In 1745, William Heberden, a London physician, wrote
a treatise decrying the use of mithridatum or its variant, the-
riac, calling it a heap of discordant simples (9). In the late
nineteenth century, Potter gave a formula for mithridatum,
adding that it was of historical interest only (7). In the twen-
tieth century, Sollman noted in his Manual of Pharmacology
that some odoriferous drugs, such as assafoetida and vale-
rian, used since antiquity, were often effective in emotional
disorders, and suggested that the effect was through olfac-
tory reflexes (10).
Plants Used in Mithridatum
Although mithridatum came to be considered a useless
mixture of plants, examination of the list with our current
knowledge of secondary metabolites of plant compounds
and extracts gives a different picture. There must have been
considerable effort made originally to select plants that con-
tained ingredients believed to be useful remedies. The meth-
od of selection seems to have included plants in three catego-
ries: plants in which selected portions were very odoriferous;
plants that had been shown by trial and error to have useful
actions; and plants of the family Apiaceae (Umbelliferae),
members of which are recognized by the characteristic shape
of the flowering head (called an umbel). This family contains
many plants that synthesize flavones and flavonols (11). Of
the thirty-one plants listed in Table 1, eight are members
of the Apiaceae, a number not to be expected by random
selection of odoriferous plants. In addition, none of the plants
contain significant amounts of bioactive alkaloids. Even the
wild poppy, Papaver rhoeas, does not contain opium alka-
loids in any quantity, although opium was substituted for the
European wild poppy in some of the later versions. Alkaloids
were excluded because they were considered poisons. Many
plants containing bioactive alkaloids were well known in
antiquity, such as those containing atropine, aconitine, coni-
ine, and the opium alkaloids.
Table 1 lists thirty-one of the thirty-four plants in Celsuss
version. ThreeIllyrian iris (Iris germanica), darnel (Lolium
temulentum), and rhubarb (Rheum ponticum)have been
excluded because they were not commonly represented in
other versions of mithridatum that were examined. [The scien-
tific names of the plants have been taken from the translation
Table 1. Continued
Scientific Name Plant Family Common
Name
Part Used
a
Bioactive
Ingredient
Chemical
Category
Mechanism
b
Papaver rhoeas L. Papaveraceae Wild poppy Juice from
herb (47)
Extract Antioxidant properties
(48)
Petroselinum
crispum (Mill.) Nym.
Apiaceae Parsley Leaf, seed (11) Apigenin
and fisetin
flavonoids inhibit production of IL-4
and IL-13 (49)
Pimpinella anisum L. Apiaceae Anise Seed (11) Anethole furanocoumarin anti-inflammatory activity
(50)
Piper longum L. Piperaceae Long
pepper
Fruit, seed
(51)
Extract Fruit extract reduces lipid
peroxidation (51)
Pistachia
terebinthus L.
Anacardiaceae Terebinith Resin (52) Masticadi
enonic acid
triterpene inhibits leukotriene B4
production (53)
Rosa gallica L. Rosaceae Gallic rose Leaves,
flowers (13)
Gallic acid phenolic acid antioxidant (54)
Saussurea costus
(Falc.) Lipsch
Asteraceae Costus Root (55) Costunolide sesquiterpene lac-
tone
blocks NO and NF-B
activation (56)
Seseli libanotis Apiaceae Hartwort Root (57) Pteryxin coumarin shows strong antiplatelet
aggregation activity (46)
Valeriana celtica L. Valerianaceae Celtic nard Root (58) Valerenic acid sesquiterpene soporific activity (59)
Zingiber officinale
Rosc.
Zingiberaceae Ginger Rhizome (60) 6-Gingerol phenyl propane
ketone
suppresses NFB
binding (16)
a
The reference identifies the bioactive ingredient in the plant.
b
The reference gives the bioactivity of the ingredient.
c
Fisetin is also found in parsley.
d
Imperatorin
is also found in parsley, anise and opopanax.
e
Coniferyl aldehyde is also found in assafoetida.
f
Gallic acid is also found in the Gallic rose.
g
Ferulic acid is also
found in lesser centaury.
64
by Spencer (4).] For each of the plants in Table 1 a major
secondary metabolite is listed that has been reported to have
bioactivity, based on examination of the current scientific
literature; the Tables references are far from exhaustive. The
intent is to provide a recent reference that suggests a possi-
ble explanation for the popularity of mithridatum for wounds,
bruises, and gastrointestinal aliments in the historical period
when mechanisms of drug action were unknown.
Evaluation of Mithridatum
The obvious characteristic of many plants in Table 1 is that
they are odoriferous and contain phenols or terpenes. In
regard to bioactivity, the major characteristic is that their
extracts, or secondary metabolites obtained from the plants,
have been reported as reducing inflammatory responses
through mechanisms that vary from scavenging free radicals
to inhibiting the inflammatory cascade by blocking activation
of nuclear factor B (NF-B). Chemicals in nine of the plants
in Table 1 have been reported to scavenge reactive oxygen
species (ROS): sweet flag, lesser
centaury, cinnamon, saffron,
hypocistis, assafoetida, storax,
poppy, and gallic rose. Other
plants contain compounds that
inhibit production of nitric oxide
(NO) (i.e., myrrh, sweet rush,
and costus), or inhibit produc-
tion of inflammatory cytokines,
(i.e., acacia, frankincense, pars-
ley, and terebinth), or reduce
inflammatory reactions by inhibi-
tion of platelet aggregation and
lipid peroxidation (i.e., myrrh,
cardamon, Indian nard, opo-
panax, long pepper, and hartwort). Four of the plants
Cretan carrot, parsley, anise, and opoponaxcontain
imperatorin, a furanocoumarin that has been shown to inhib-
it binding of the nuclear factor of activated T-cells (NFAT) to
DNA. Costunolide and dehydrocostus lactone, found in cos-
tus, block activation of NF-B, as do the gingerols in ginger
root and 2-hydroxy cinnamaldehyde in cassia, thus reducing
production of several components involved in the inflamma-
tory response, such as inducible cyclooxygenase-2 (COX-2)
(see Table 1 for references).
Current information on plant defensive compounds suggests
that anti-inflammatory effects might have resulted from tak-
ing mithridatum for certain kinds of illness. There are reports
describing a positive relationship between serum levels of
antioxidants and antioxidant enzyme levels associated with
intake of plants or extracts (12, 13). This association sup-
ports the concept that some of these plants may be chemo-
protective against oxidative stressmediated disorders (14,
15). Local anti-inflammatory effects are also possible from
topical use. For example, application of 6-gingerol to skin
reduces COX-2 expression (16).
There are several difficulties, however, in evaluating a formu-
la of mithridatum for anti-inflammatory activity; for example,
the plant species for which data have been obtained in Table
1 may not be identical in chemical content to species grow-
ing in different localities centuries ago, even if the identifica-
tion of the species is correct. The methods of preparation of
the plants after they were gathered might also have an effect
on chemical constitution, and the degree of maturation of the
plants at the time they were gathered may have affected the
concentrations of secondary metabolites. The possibility that
synergism exists among ingredients acting at the same or dif-
ferent loci is uncertain. The use of several plants containing
chemicals affecting different portions of the inflammatory pro-
cess may increase or decrease the likehood that the desired
effects would be produced.
Conclusions
The change in character of mithridatum over the centuries is
noteworthy. The formula examined here is one of the oldest
and presumably closest to the one Mithridates concocted
from his own knowledge and with the advice of Zopyrus.
Later versions seem to have been less focused on ingredients
with anti-inflammatory properties,
perhaps arising from a lack of
empirical evidence of effectiveness
or through a desire to develop a
new and better version. Later
additions often were of animal
tissues, such as dried blood and
dried viper or lizard flesh (17).
The idea seems to have been that
some animals must be immune to
their own poisons and that this
immunity could be transferred.
Additional plants were added and
some old ones removed as plants
more easily obtained in Europe
were substituted for ones from the East. These changes might
have diluted the effectiveness of bioactive ingredients in the
original version, and it is not surprising that use of mithrida-
tum disappeared by the end of the nineteenth century. There
is no convincing evidence from the past that mithridatum was
either useful or useless as a remedy for some conditions. It
is true that each formula was carefully designed to produce
a useful remedy by the standards of the period. Although
modern copies of these formulae could be made and tested,
these versions could not be proved to be the same as older
versions because data on content of secondary metabolites in
old varieties of plants cannot be obtained. Nevertheless, it is
Reflections
Wild Poppy
Anise
65
April 2006
Volume 6, Issue 2
interesting to speculate about Theophrastuss claim that mega-
lium could have alleviated the inflammation from any wound,
and it is possible that the early versions of mithridatum, such
as the one reported by Celsus, were useful in some inflamma-
tory conditions. doi:10.1124/mi.6.2.1
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Reflections
Stata Norton, PhD, is
an Emeritus Professor in the
Department of Pharmacology,
Toxicology, and Therapeutics,
University of Kansas Medical
Center, Kansas City, KS.
She has published over 120
research articles, reviews, and
book chapters on neurophar-
macology and neurotoxicology,
especially on the effects of drugs and radiation on the devel-
oping central nervous system. E-mail snorton@kumc.edu; fax
(913) 5887501.