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Pharmacology and psychiatry at the origins of Greek medicine: The myth of Melampus and the madness of the Proetides

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Melampus is a seer-healer of Greek myth attributed with having healed the young princesses of Argos of madness. Analysis of this legend and its sources sheds light on the early stages of the “medicalizing” shift in the history of ancient Greek medicine. Retrospective psychological diagnosis suggests that the descriptions of the youths’ madness rose from actual observation of behavioral and mental disorders. Melampus is credited with having healed them by administering hellebore. Pharmacological analysis of botanical specimens proves that Helleborus niger features actual neurological properties effective in the treatment of mental disorders. The discussion aims at examining the rational aspects of the treatment of mental conditions in Greco-Roman antiquity.
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Journal of the History of the Neurosciences
Basic and Clinical Perspectives
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Pharmacology and psychiatry at the origins of
Greek medicine: The myth of Melampus and the
madness of the Proetides
Matteo F. Olivieri, Francesca Marzari, Andreas J. Kesel, Laura Bonalume &
Francesco Saettini
To cite this article: Matteo F. Olivieri, Francesca Marzari, Andreas J. Kesel, Laura Bonalume &
Francesco Saettini (2017) Pharmacology and psychiatry at the origins of Greek medicine: The myth
of Melampus and the madness of the Proetides, Journal of the History of the Neurosciences, 26:2,
193-215, DOI: 10.1080/0964704X.2016.1211901
To link to this article: http://dx.doi.org/10.1080/0964704X.2016.1211901
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Pharmacology and psychiatry at the origins of Greek medicine:
The myth of Melampus and the madness of the Proetides
Matteo F. Olivieri
a
, Francesca Marzari
b
, Andreas J. Kesel
c
, Laura Bonalume
d
,
and Francesco Saettini
e
a
Department of Historical Studies, University of Milan, Milan, Italy;
b
Centro Antropologia e Mondo Antico, University
of Siena, Siena, Italy;
c
Pharmacist, Munich, Germany;
d
Department of Psychology, University of Milano-Bicocca, Milan,
Italy;
e
San Gerardo Hospital, Department of Pediatrics, University of Milano-Bicocca, Milan, Italy
ABSTRACT
Melampus is a seer-healer of Greek myth attributed with having healed
the young princesses of Argos of madness.Analysisofthislegendandits
sources sheds light on the early stages of the medicalizingshift in the
history of ancient Greek medicine. Retrospective psychological diagnosis
suggests that the descriptions of the youthsmadness rose from actual
observation of behavioral and mental disorders. Melampus is credited
with having healed them by administering hellebore. Pharmacological
analysis of botanical specimens proves that Helleborus niger features
actual neurological properties eective in the treatment of mental dis-
orders. The discussion aims at examining the rational aspects of the
treatment of mental conditions in Greco-Roman antiquity.
KEYWORDS
Greek myth; Melampus;
Proetides; hellebore;
madness; pharmacology;
retrospective psychological
diagnosis
Introduction and methodology
The mythical Greek seer-healer Melampus was known for having healed from madness
three maidens the daughters of the King Proetus by administering hellebore. This
legend has prompted us to revise the legends regarding Melampus in light of the ancient
history of neuropsychiatry and pharmacology. The medical aspects embedded in the myth
of Melampus have already been the subject of research (Marenghi, 1960; Nogueras, 2002;
Costanza, 2009,2010; Marzari, 2010,2012), but the use of hellebore specically as a
psychoactive remedy does deserve closer analysis. We have addressed these issues by
interdisciplinary methodology. Ancient history and philology explain the dierent ver-
sions of the myth as described in the literary sources and document the use of hellebore in
Greek and Roman medicine. The data are investigated in the perspective of the diagnosis
of mental or neurological disorders. A pharmacological analysis of the compounds in the
Helleborus plant genus substantiates the possibility of its use as an herbal medicament.
The myth: Melampus healing the Proetides from madness
Melampus is a renowned seer (mantis) and healer of ancient Greek myth. His endeavors are
preserved in literary sources from Homer to the Roman Imperial period (eighth century BC
CONTACT Matteo F. Olivieri matteofulvio.olivieri@gmail.com Department of Historical Studies, University of
Milan, Via Moscoretto 2, Cernusco Lombardone (LC), Milan 23870, Italy.
Color versions of one or more gures in this article are available online at www.tandfonline.com/njhn.
JOURNAL OF THE HISTORY OF THE NEUROSCIENCES
2017, VOL. 26, NO. 2, 193215
http://dx.doi.org/10.1080/0964704X.2016.1211901
© 2017 Taylor & Francis
fth century AD) as well as in later lexicographical tradition.
1
Indeed, in the sixth century BC
epic poem Melampodia, most of the seers of Greek heroic tradition are credited as being
descendants of Melampus (Hesiod, fr. 270279; Löer, 1963; Burkert, 1987; Cozzoli, 2007;
Flower, 2008;IlesJohnston,2008). Melampus was born the son of the King of Pylos,
Amythaon, and he was cousin to Jason, the famed leader of the expedition of the Argonauts
(Apollodorus, Library, 1.9.11, 14 and 16; Diodorus Siculus, 4.68.34). The origin of
Melampusprophetic skills is related particularly in one legend: Melampus reared some
youngling snakes from a lair that had been destroyed by his servants and, in gratitude, the
snakes as he slept, purged his ears with their tongues and having fallen in with Apollo [.. .] he
was ever after an excellent soothsayer(Apollodorus, Library,1.9.11).
Melampus put these arts to use while stealing cattle from Phylacus and his son Iphicles:
He took on the task of retrieving the cattle back from Thessaly for King Neleus of Pylos
but was imprisoned by the King Phylacus of Thessaly, yet Iphicles released him, when he
had told all the oracles(Homer, Odyssey, 9.296f.).
A later version of this legend shows evidence of Melampusskills not only as a seer but
also as a healer: after his extraordinary liberation, he is said to have cured Iphiclessterility
(Apollodorus, Library, 1.9.12. Costanza, 2010; Marzari, 2012).
One renowned episode from the mythical biography of Melampus is the healing of the
young daughters of Proetus, the King of Argos (or of Tiryns, according to Bacchylides,
Epinician, 11.5781), known in tradition as the Proetìdes.
2
When these girls reached the
age of marriage, they oended the gods and, thus, were punished with madness, subse-
quently eeing from their home and from human society (Marzari, 2010,2012). Dierent
sources attribute the responsibility for the girlsmadness to dierent gods: according to
Hesiod, it was Dionysus, who the Proetides had angered by refusing to worship him
(Catalogue of Women, fr. 131 M.-W.; see Fig. 1). Bacchylides sung instead of the ven-
geance of Hera, because the princesses had despised (or oended) the richness of her cult-
statue (Epinician, 11.4257; also Apollodorus, Library, 2.2.2); also, Aphrodite is cited
among the oended deities (Aelian, Historical Miscellany, 3.42).
Regarding the girlsbehaviors or symptoms, later Latin versions of the myth also say
that the girls believed to have been transformed into heifers, so they went around in the
wild mooing (Vergil, Eclogues, 6.4754). In Hesiods eighth- to seventh-century BC
version, there are also references to lust (machlosùne), vitiligo (alphòs), and a form of
itch (knùos) that caused hair loss, that is, alopecia (Catalogue of Women, fr. 132f. M.-W.)
(Fig. 2 from Libertini, 1950; see Casadio, 1994; Marzari, 2010,2015).
According to another legend, the madness also spread to all of the women of Argos,
who also abandoned their houses, destroyed their own children, and ocked to the
desert(Apollodorus, Library, 2.2.2).
3
1
Main references in Homer, Odyssey, 11.291, 15.225., 238.; Hesiod, fr. 131 M.-W.; Acusilaus, FGrH 2F
28; Pindar, Paeans, 4.2830; Scholion to Pindar, Nemean, 9.13; Pherecydes, FGrH 3 F 114; Herodotus,
9.34; Diodorus Siculus, 4.68; Pliny, Natural History, 10.137; Apollodorus, Library, 1.9.1112, 2.2.2;
Pausanias, 2.18.4; Suda, s.v. MelàmpousM 448, s.v. SýmbolonS 1376; Clark, 2012; Käppel, 2015.
2
Main references to the group of maidens: Hesiod, fr. 130 M.-W. = Strabo 8.6.6; Ovid, Metamorphoses,
15.325f.; Vergil, Eclogues, 6.48; Strabo, 8.3.19; Pausanias, 5.5.5; Athenaeus, 8.24. The myths connected
to the Proetides are expounded in How and Wells (1928): ad Herodotus 9.34.
3
See also Herodotus, 9.3334; Diodorus Siculus, 4.68.4; Apollodorus, Library, 1.9.12; Pausanias, 2.18.4.
194 M. F. OLIVIERI ET AL.
Melampus agreed with King Proetus to cure his daughters and was rewarded by receiving
one of the princesses in marriage, one third of the kingdom for himself, and also the same for
his brother Bias: so both of them became rulers of the kingdom of Argos (Diodorus Siculus,
4.68; Pausanias, 2.18.4; see also Homer, Odyssey,15.236244; Herodotus, 9.34; Dorati, 2004;
Flower, 2008).
The measures taken and therapy by which Melampus treated the Proetides vary amongst
versions of the myth. According to the most documented tradition, Melampus healed their
madness resorting to his skills as a seer: performing prayers, rituals, sacrices, fumigations, or
Figure 1. Melampus and the healed Proetides in a sanctuary in the presence of Dionysus. Photograph:
Lucanian Nestoris. Napoli, Museo Archeologico Nazionale, inv. H 1760 (2. inv.), 82125 (1. inv.). Ca 390
370 BC. © Auctores Varii (1994, p. 413).
Figure 2. Melampus treating the Proetides by sacricing a piglet: A bald girl on the right might be a
reference to the Proetidesalopecia described by Hesiod. Sicilian Calyx Krater, from Canicattini. Siracusa,
Museo Regionale 47038. Ca 350-325 BC. © Libertini (1950, p. 101).
JOURNAL OF THE HISTORY OF THE NEUROSCIENCES 195
ablutions in the waters of rivers and springs in which he had cast remedies.
4
The mytho-
grapher Apollodorus (rst to second AD) describes a sort of ritualistic frenzied dance
performed by Melampus to treat the Proetides but also records that he had been the rst
to devise the cure by means of drugs and purications(Apollodorus, Library,2.2.2).
One version of the tradition owing mostly to Greek and Roman medical and
naturalistic literature preserves the notion that Melampus cured the Proetides by
administering a specic herbal remedy: hellebore (Hippocrates, Letters, 16; Dioscorides,
On Medical Material, 4.162.1; Galen, On Black Bile, 7; Oribasius, Medical Compilations,
7.26.42). Sources even provide details as to which specic variety of the herb was
employed by Melampus: black hellebore, according to most accounts, but, according to
Galen, the white variety. In the rst century AD, Pliny also associates Melampus to
hellebore with additional details and rationale:
Some persons [. . .] attribute the discovery of this plant to a shepherd of that name (i.e.,
Melampus), who remarked that his she-goats were violently purged after browsing upon it,
and afterwards cured the daughters of Proetus of madness, by giving them the milk of these
goats. (Pliny, Natural History, 25.21.47)
Mental disease in ancient Greek and Roman medical thought
In spite of dierences in the versions of the myth of Melampus, all the legends on the
Proetides and the women of Argos unanimously seem to refer to their condition as a
mental disorder either by mentioning madnessor employing other vocabulary of mental
disorders to describe behavioral disorders, delusions, or hallucinations. These references
need to be contextualized within the history of Greek and Roman thought on the
disorders of human psyche.
Mental disorders were considered at length among the Greeks and Romans (Harris, 2013).
Aspecic vocabulary for illnesses of the mind and psyche appears as early as the Homeric
sources (Perdicoyianni-Paleologou, 2009;Holmes,2010, p. 43 n.7) and it became more
articulated in the course of the classical age, both in medical and nonmedical sources: this
vocabulary is the sign of a specicscienticand even cultural interest in understanding
and categorizing such conditions. For instance, manìa is the most common term for mad-
ness,a state of frenzy,or outrageous enthusiasm.But òistros also translates as madness
but was intended as a vehement desireor inappropriate passion (Perdicoyianni-Paleologou,
2009; Thumiger, 2013; Antoni, 2016). Lýssa translates as rageor battle rageand can indeed
be considered a specic form of psychological alteration (Waldner, 2016). Melagcholikòs is an
adjective meaning of melancholic temperament,which may be likened to depression;
however, the condition originated from humoral imbalance and hence also translates as
atrabiliousor choleric(melàs +cholé, i.e., black bile) (Nutton, 2016b). Diagnosis of an
inammation of the brainwas dened as phrenìtis. Epilepsy was recognized and described
4
On the religious solutions for curing the Proetidesmadness, see Hesiod, fr. 37 M.-W., v.14; Pherecydes,
FGrH 3 fr. 114; Eudoxus of Cnidus, ap. Stephanus of Byzantium, Ethnica, s.v. Azania; Diphilus, fr. 125
PCG; Strabo, 8.3.19; Vergil, Eclogues, 6.48-51; Vitruvius, 8.3.21; Ovid, Metamorphoses, 15.326;
Apollodorus, Library, 2.2.2; Pausanias, 5.5.10, 8.18.7-8; Servius ad Vergil, Eclogues, 6.48 and Georgics,
3.550.
196 M. F. OLIVIERI ET AL.
as early as the Babylonian texts and was the specic subject of the Hippocratic De Morbo Sacro
(Nutton, 2016a).
Causes of mental illness were generally relegated to the sphere of the supernatural,
originating from the gods or from demonic possession. The gods would inict madness or
mental disorders, commonly as a punishment for misdeeds towards moral or religious
conventions; similarly, the gods could heal one from those symptoms. Madness is treated in
these terms especially in theatre, for example, Euripides (Bacchae, Hyppolitus,141144) and
Sophocles (Ajax, Trachiniae;Dodds,1965;Graf,2015).
5
Therefore, it is within this mindset that also the remedies to madness were sought: in
the supernatural, ritual, and religion, appeasing the oended deity (Nutton, 2015a,2015b).
On the other hand, already in archaic sources, madness (manìa) may have originated at a
more mundane level: from extreme human emotions, such as love or fear. As early as the
fth century BC, a shift towards rationalizationor secularizationof mental disease can
be recognized, that is, seeking explanations within the human body and psyche rather than
in the theological sphere. Harris appropriately speaks of the medicalization of mental
illness(2013). The fth- to fourth-century Hippocratic tradition is our paramount evidence
for this development (Thumiger, 2013). Indeed, the medicalizationof Greek neuroscience
was pursued by two major schools of thought, which modern scholarship has categorized as
physiologicaland psychological(Roccatagliata, 1986; Perdicoyianni-Paleologou, 2009).
The physiologicalor organicapproach explained mental diseases in terms of
physical disturbances: According to the so-called humoral theoryof Greco-Roman
physicians, when bodily uids were interrupted or altered, specic ailments would
occur, among which were even psychic conditions and symptoms. Hippocratic physicians
directed their inquiries according to this framework from the fth century BC on. In the
rst century AD, Aretaeus dedicated a specic chapter in On Madness, treating this aspect
of human psychology as a common bodily illness.
Dierently, the psychologicalapproach inquired into mental conditions rather in
terms of disturbances of the psyche or soul(Gill, 2013; Hughes, 2013). In the fth to
fourth centuries BC, Plato wrote: We must agree that folly is a disease of the soul; and of
folly there are two kinds, the one of which is madness (manìa), the other ignorance. [. . .]
[I]t must be termed disease(nòsos)(Timaeus 86b; see the discussion in Jouanna, 2013).
Given these medicalizedconceptions of the causes of madness and other mental illnesses,
the treatments also shifted towards physical remedies: more commonly, physical constraint,
diets, or mental and moral training (Nutton, 2015b); administration of drugs was known, but
scholars believe it was rather limited (van der Eijk, 2013; see also Harris, 2013).
These developments in Greek medicine should not be seen as independent one from the
other, nor as a teleological evolution of ancient medicine: rather, they were the result of a
diversication of rationalisticthought. Indeed, the secularization of madness was paired with a
broadening and blurring of its semantics: for instance, Plutarch (rst century AD) associated
manìa to mental dispositions and feelings as broad as love, anger, and even drunkenness
(Plutarch, Amatorius,16,De Sollertia Animalium,5,De Garrulitate,4).Moreover,inparallel
5
Essentially Greek tragedy conforms to a rather conservative attitude towards madness and mental
illnesses in general, both in its vocabulary as well as in the way cause and eect are expounded: This,
of course, owes to the literary genre, topics, and performance context. On this matter, see
Papadopoulou (2005, p. 59) and Holmes (2010, pp. 255274, 231).
JOURNAL OF THE HISTORY OF THE NEUROSCIENCES 197
to the inquiry of physicians and philosophical schools, religion and tradition remained a
hermeneutic tool for the understanding of the human condition: magic, oracular consulting,
templar incubation, and Asklepian cult were always staples of Greek and Roman healing
practices and the more so of neuroscience. They did indeed ourish in Hellenistic times and
should not be understood in a dichotomy to medical practices.
What is tantalizing about the myth of Melampushealing of the Proetides is that there
seems to be a consistent presence of medicalizedelements and attitudes throughout all
the narratives, regardless of their antiquity or source, and, moreover, they include details
on the administration of the medicinal drugs.
Hellebore in ancient Greek and Roman medicine
Herbal remedies were generally well known in Greco-Roman antiquity (Nutton, 2015a)
and, among them, hellebore was one of the most noteworthy. Its use is widely attested as
of fth-century popular and medical sources (Hünemörder, 2015).
6
Alone or as an
ingredient in medicinal concoctions, hellebore was associated with the broadest variety
of medicinal uses, for example, in skin treatments, as a colic remedy, in curing hydro-
phobia, alopecia, headaches, epilepsy (Keyser & Irby-Massie, 2008), and also hysterical
suocation (Hippocrates, Diseases of Women, 2.123126).
One of the more commonly attested prescriptions of hellebore was as a purgative
(Hippocrates, Aphorisms, 4.13, On Regimen in Acute Diseases, p. 7; Theophrastus,
Enquiry into Plants, 9.10.24; Dioscorides, On Medical Matters, 1.9, 2.75, 4.76, 4.150,
4.151, 4.152, 4.158, 4.171; Pliny, Natural History, 25.21; Aretaeus, On the Therapeutics of
Chronic Disease, 2.7). This is also its earliest historical recorded use: in 600 BC, the
Athenians would have adulterated the drinking water of Cyrrha with hellebore and were
able to take the besieged city unguarded (Pausanias, 10.36.7, 37.7; Robertson, 1978,p.69
n.5; Girard, 1986, p. 49).
According to Greek humoral theory, hellebore had the property of inducing heat in the
intestines and viscera: hence, the Corpus Hippocraticum widely prescribes it in treating
humoral imbalances and, as such, even in treating madness and neurological or psychia-
tric conditions (Letters, 16; Girard, 1986, esp. p. 127). In Aretaeuschapter on the Cure of
Melancholy,hellebore is prescribed when a disorder seizes the nerves [. . .] and engen-
ders spasms, mania, paralysis(1.5). Indeed, this use persisted beyond antiquity and well
into the nineteenth century of the modern era (Girard, 1986).
The role of hellebore as a cure for madness reported in the narrative on the Proetides is
the more pertinent in light of Greek gynecological theories. Hellebore was in fact con-
sidered to have emmenagogue and abortive properties and was prescribed in ancient
6
For references in medical and scientic literature, see Theophrastus, Historia Plantarum, 9.10.14, 14.4;
Pliny, Natural History, 13.114, 25.48, 27.76; Dioscorides, On Medical Matters, 1.1, 1.9, 2.75, 4.76, 4.77,
esp. 4.150 and 4.151, 4.152, 4.158, 4.171, 4.186; Aretaeus, De curatione acutorum morborum libri duo.
For reference in nonmedical genres, see, for instance, Aristophanes, Wasps, 1488f.; Plato, Euthydemus,
299b; Aristotle, Nicomachean Ethics, 5.9.15; Demosthenes, On the Crown, 18.121; Strabo, 9.3.3;
Epictetus, Discourses, 2.15.14; Plutarch, Moralia, 48e74e, 452f464d, 612c748d, 1058e1086b;
Pausanias, 10.36.7, 37.7. Indeed, Greek physicians are known to have dedicated whole books to
hellebore: Pseudo Demokritos (15050 BC), Agathinos of Sparta (3070 AD), Arkhigenes of Apameia
(95115 AD). See Keyser and Irby-Massie, 2008, pp. 42, 160, 238.
198 M. F. OLIVIERI ET AL.
gynecology to ease menstrual blood ow (Dioscorides, On Medical Material, 4.162.23)
thereby avoiding hematic blockage (Marzari, 2010). Young girls reaching the age of
puberty, such as in the case of the Proetides, were known to be prone to a form of
delusion caused by excess blood accumulating in the body because of menarche (see the
Hippocratic work, On the Diseases of Virgins; Andò, 1990; Guidorizzi, 1995; Faraone,
1999). Among the symptoms of the Proetides, Hesiod also mentions vitiligo (alphòs), and,
in the Corpus Hippocraticum, this sign is described as a humoral outlet (apòstasis)of
phlegmatic origin (Epidemics, 2.1.7; On Aections, 35). Hence, it would seem that helle-
bore would have been a particularly tting prescription in the case of the Proetides. An
excess of phlegm was also believed to be the origin of another two of the ailments
attributed to the Proetides: hair loss and itching (knùos). Thanks to its purgative proper-
ties, hellebore was indeed recommended for eliminating excessive phlegm and restoring
humoral balance. In addition, as a cataplasm, hellebore was used against alphòs and other
kinds of dermatosis (Marzari, 2015).
Hellebore is also documented as a cure for madness and neurological conditions in a
great deal of Greek and Latin nonmedical and nonscientic sources. Indeed, the rst
attestation of its use can be traced to Aristophanesplay The Wasps, performed in Athens
in 422 BC (Aristophanes, Wasps, 1488f; see also Demosthenes, On the Crown, 18.121;
Plautus, Pseudolus, 4.7.8085, Rudens, 4.3.7074; Horace, Satires, 2.3.82; Svetonius,
Caligula, 29; Plutarch, Quaestiones Conviviales, 6.7. [Morals 693a]; Epictetus, Discourses,
2.15.14). The association of hellebore to cure insanity seems to have been so commonplace
throughout Greco-Roman culture that advising one to take some helleborewas a
proverbial expression implying they were speaking or acting foolishly or outrageously
(Thomson, 1835, p. 811; Botsford & Sihler, 1915, p. 523). Moreover, according to Pliny,
studious men are in the habit of taking hellebore for the purpose of sharpening the
intellectual powers, it is known as a cure for epilepsy, and in combination with radicula
[. . .] to act as a sternutatory, and are both of them productive of narcotic eects(Natural
History,25.21.5153).
It is consequential, then, that the neurological properties are attested and widespread in
prosaic texts and popular culture and that the earliest attestations are in Attic comedy. It
may be taken as evidence that a commonplace, longstanding, oral and popular tradition
concerning this herbal remedy existed in Greek culture.
In the light of the possibility of such longue durée of popular knowledge, the place of
hellebore as a cure for madness in Greek myth gains additional signicance. The etiology
of the discovery of hellebore is in fact placed in a mythical setting and is related to
Melampus (Ps. Hippocrates, Letters, 16.5052; Theophrastus, Enquiry into Plants, 9.10;
Dioscorides, On Medical Material, 4.162; Pliny, Natural History, 25.2125). The very
etymology of hellebore is associated with this mythical character: black hellebore was
called melampòdion after him and was also known as the black root(melanòrrhizon)
(Edmunds, 1981). As a cure for madness, hellebore was also used by the eponymous hero
Antikyreus to cure Herakles of his murderous bout of madness (Ps. Hippocrates, Letters,
16.5052; Photius, Library, 177a 3336 Bekker; see also Pindar, Isthmian, 4.63f.; Euripides,
Heracles, 967.). These mythological attestations may be taken to indicate that the Greeks
themselves traced the discovery of the neurological properties of hellebore as far back as to
their own prehistory and considered the herb an age-old medicament for madness.
JOURNAL OF THE HISTORY OF THE NEUROSCIENCES 199
The mental condition of the Proetides: Purpose and pitfalls of retrospective
diagnosis
Ancient sources are consistent in attributing the Proetides with madness: this is, in fact,
their essential feature in all the narratives. In order to explain what the ancient sources
were actually describing, we may attempt a retrospective diagnosis, on the grounds of the
behaviors ascribed to the maidens, in light of clinical psychology and despite the cautions
and pitfalls of such an experiment might seem deterring.
It should not go unsaid that the Proetides are characters of literary creation and by no means
patients.The events and behaviors attributed to the Proetides may well have originated
altogether from literary and cultural models. For instance, the girlsmadnesscomplieswith
literary leitmotifs of the crisis of womens place in society: their rebellion towards the burdens of
married status or initiation rites of youth before marriage (Farnell, 1896;Burkert,1987,pp.
472484). Also, the element of divine punishment by madness may be a reection of ancient
mythic-ritual schemes: indeed, DionysusisresponsiblefortheProetidesfury in certain versions
(Catalogue of Women, fr. 131 M.-W.) and this gods rites did involve ecstatic practices of self-
induced agitation (Burkert, 1987, pp. 235237, 318326). In addition to this, we must keep in
mind what profound linguistic, cultural, and scienticdierences divide our sourcesback-
grounds from the parameters of modern neuroscience. Nonetheless, we believe it can prove
useful to explore a retrospective diagnosis in the multidisciplinary methodology of this research:
the symptoms discernible in the girlsbehavior may relate to a number of psychopathological
disorders and organic diseases (Vieta & Phillips, 2007).
Until the early-nineteenth century, the symptoms displayed by the Proetides would have
been related to the traditional nosologic denition of adolescent hysteria,caused by severe
uterine melancholy(Lefkowitz, 1981; Tasca et al., 2012). If we considerthe sisters as a group,
and more so if we consider the involvement of the Argive women, we may otherwise consider
adenition of mass hysteria.But dierent denitions for symptoms once relating to hysteria
have been devised over the course of the twentieth century: conversion symptoms, melan-
choly, mania, mood disorders, hebephrenia, catatonia, paranoia, psychosis, histrionic person-
ality disorders, or dissociation. However, conversion symptoms required for a diagnosis of
typical hysteria cannot be evidenced in the narrative of the myth.
Since the 1980s, Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-
III; American Psychiatric Association, 1980) hysterical neurosis has been considered as the
manifestation of dissociative disorders. According to Diagnostic and Statistical Manual of
Mental Disorders,fth edition DSM-V (American Psychiatric Association, 2013), these
behaviors may be referred to the denition of depersonalization,that is, as experiences of
unreality, detachment, or being an outside observer with respect to ones own thoughts,
feelings, sensations, body, or actions (perceptual alterations, distorted sense of time, unreal or
absent self, emotional and physical numbing). The average age of the onset of depersonaliza-
tion is 16, close indeed to the Proetideslikely age of marriage (on the girlsage, see Ingall,
2001). Dissociative disorders have high comorbidities both with mood disorders and with
personality disorders, such as borderline ones, that commonly co-occur. It is important to
understand the features of delusional and psychotic symptoms (even induced by drug abuse):
the presence of intact reality testing specically regarding the depersonalization symptoms is
essential to dierentiating them from psychotic disorders. In the case of the Proetides, some
traditions do mention that they are believed to have been transformed into heifers and to have
200 M. F. OLIVIERI ET AL.
wandered into the wilderness, but these could be subjective experiences recognizable by the
patient as abnormal or delusional. Similarly, borderline patients may show both psychotic (as
temporary decit of reality testing) or depersonalization/derealization symptoms, not actually
a pathognomonic of psychotic or delusional disorder but relevant from a phenomenological
point of view.
Hesiod describes the symptoms of lust, vitiligo, and itch: these may be interpreted as
signs of careless sexual behavior (lust) and as the somatic outcome of bodily negligence
(vitiligo and dermatosis); Ntafoulis, Gourzis, and Trompoukis (2008) relate these to a
psychosomatic expression of anxiety, distress, and melancholy.
Taking into consideration, on the whole, the dierent versions of the myth, we can observe
oensive, insulting or damaging behaviors, wantonness, and lust: these symptoms may be
consistent with the modern diagnosis of a manic episode, typical of Bipolar I disorders.
Ancient sources also mention eeing and erratic wandering, believing to have been trans-
formed, screaming or even mooing: within the abovementioned diagnosis of a mood disorder,
these symptoms may be attributed to psychomotor agitation and psychosis. Therefore, the
condition of the Proetides could be explained as a complex mood disorder within the classic
denition of severe maniac-depressive or aective psychosis(Kraepelin, 1915).
In our opinion, the psychotic symptoms in the myth cannot be referred to as a pure denition
of psychotic or schizophrenic disorder, according to both the phenomenological denition of
hebephrenia, catatonia, or paranoia and to the nosographic descriptions according to the DSM
model. Firstly, the myths do not seem to describe any of the negative symptoms, such as alogia,
anhedonia, avolition, typical of a schizophrenia spectrum. Moreover, the typical timing of
schizophrenia onset does not correspond to the girlslate-adolescent age.
Psychosis, restlessness, skin lesions, and hair loss are, among others, well-known
symptoms of systemic lupus erythematosus (SLE); psychosis especially points to a diag-
nosis of central nervous system (CNS) lupus which may present also with headaches,
confusion, fatigue, depression, seizures, strokes, vision problems, mood swings, and
diculty concentrating. Vitiligo is a dermatological disorder characterized by hypopig-
mented patches of the skin that tend to become progressive over time. Both conditions are
currently explained as autoimmune disorders. A provocative paper has suggested a
possible genetic connection between SLE and vitiligo through a potentially informative
genomic region at 17p13, which may contain the putative gene, SLEV1, for vitiligo-related
SLE (Nath, Kelly, & Namjou, 2001). Although genetic commonality between some cases of
SLE and vitiligo has been proposed (Nath, Majumder, & Nordlund, 1994), the exact
pathogenic mechanism has not yet been exhaustively explained.
Other CNS-related conditions, apart from CNS lupus, might be considered but the very
nature of our case and sources does not provide enough elements for serious considera-
tion or discussion. Temporal epilepsy seems to be very unlikely to occur at the same time
and with the same features in all the women. Intoxication would imply that only the
maidens or the women of the city were exposed to the toxin, sparing the rest of the
population. Frontal lobe syndrome would need to have been anticipated by a trauma or
followed by the death of the characters (in case of neoplasm).
In all legends, the Proetides display a reckless or violent state of mind not to speak of
the infanticide, in the case of the Argive women wantonness, wandering bouts, and
overall dissociation from organized society. These behaviors could be interpreted as failure
to conform to social norms, impulsivity, irritability and aggressiveness, and protracted
JOURNAL OF THE HISTORY OF THE NEUROSCIENCES 201
irresponsibility, apparently, therefore, consistent with the diagnosis of an antisocial per-
sonality disorder. But this type of diagnosis is only valid if the behavior pattern develops
early in life, and the ancient sources do not allow for discussion on this aspect of the girls
anamnesis.
In conclusion, all of the medical considerations just mentioned require a heavy amount
of caution regarding retrospective diagnoses. This is well set out by M. Grmek (1983): A
retrospective medical diagnosis must rely on all of the symptoms, must explain the core of
the involved symptoms, not contradicting any, and comply with the epidemiological
conditions of the given period. Admittedly thus, the diagnoses we may draw here for
the Proetides should be taken as speculative at best. Respecting the very strict standards
advocated by M. Grmek, it might be safer to limit the diagnosis of the Proetidesto a
manic episode within a bipolar disorder.
This experiment in retrospective diagnosis can hardly point to any one specic diag-
nosis; indeed, we do not believe there would be a point in providing one for personages of
legend. And yet such an attempt has served the purpose of our research: by showing that
the descriptions of the Proetidesconditions and symptoms do seem to fall or may at
least be pondered within modern recognizable diagnostic features. This is signicant. If
it holds true, we may infer that the ancient authors, in setting about to describe mythical
young girls aicted by madness,were not simply creating a pastiche of outlandish
psychic conditions and outrageous actions: it would seem that the authors were indeed
constructing their literary depictions according to real-life models of symptoms and
behaviors. Perhaps these literary descriptions even in the nonmedical sources did
owe the fact that Greek medical and psychological thought took care to observe and
identify mental conditions. A retrospective diagnosis can therefore contribute to under-
standing the level of awareness the Greeks and Romans had of the existence of recogniz-
able if not explainable mental disorders and their symptoms.
Pharmacology: Medical and neurological properties of hellebore
We have brought to light the pervasive presence of hellebore as an herbal remedy in Greco-
Roman culture and, especially, as a cure for madness (Girard, 1986; Amigues, 2006,ad
Theophrastus, Historia Plantarum,9.10).Thiskindofmedicalandpopularknowledgecould
be further understood by verifying the applications and properties of hellebore, as testied in
ancient sources, against modern pharmacological tests on the compounds contained in the
helleborus plant. Unfortunately, this is not as straightforward as it may seem: since the nine-
teenth century, there has been little agreement among scholars as to exactly what plant in fact
even what species should be identied as the hellèboros of Greek sources or the helleborus of
Latin sources (Girard, 1986). Conclusions are hampered by a series of preliminary cautions.
To begin with, ancient Greek and Latin sources are inconsistent, imprecise, or contra-
dictory in describing the morphology of the hellebore plant, in establishing the dierences
between the two varieties of black and white hellebore, in attributing specic medical
eects and properties, and in identifying what parts of the plant should be used in the
preparations. Ancient authors more often wrote on the grounds of nonautoptical inves-
tigation, collating second-hand information written or oral and, in many cases, they
provide alternative versions with no critique. For instance, one of our major sources of
information on hellebore TheophrastusHistoria Plantarum though the work of a
202 M. F. OLIVIERI ET AL.
botanist, only supercially investigates and reports on the medical properties of the plants
described (Amigues, 2006,ad Theophrastus, Historia Plantarum, 9.10).
7
The professional
gatherers of medicinal plants (known as the rhizotòmoi: the root cutters) had all the
interest to secretively withhold information on the whereabouts and on the means to nd,
to identify, to gather, and to preserve their prime materials. Therefore, even physicians
and the authors of our written sources should be presumed to have accessed hellebore
only in its commercial forms: ground, pulverized, decocted, etc., that is, heavily altered
if not unrecognizable from its natural form (Deroux, 1976, p. 876).
In a perspective other than textual and historical contextualization, considerations on
the history of the environment and ora call for further caution. In the course of the
centuries, there have been massive changes in the environment, climate, and ora of the
Mediterranean: natural and induced climate change, modication of temperatures, retreat-
ing mountain snow lines, deforestation, anthropization, depletion and erosion of soils,
exhaustion of rare oral resources, and introduction of allotrope species, to name but a
few. We can hardly hope to employ modern records on the ecosystems to reconstruct the
ora of antiquity. The hellèboros (Greek) and helleborus (Latin) described by ancient
sources may well no longer be endemic to Greece today, or, vice versa, we may in our
day come across allotrope varieties of the plant, so running the risk of an anachronistic
identication.
Archeobotanical and chemical analysis of ancient material evidence (e.g., trace contents
in pottery and nàrthekes, i.e., drug chests) could unlock useful data. Alternatively, research
could undertake a critical review of antique-nineteenth- and early-twentieth-century
botanical surveys and herbaria as a means of accessing more pristine environments of
preindustrialized Greece (Sibthorp & Smith, 1825; de Halàcsy, 1900). Both these options
would encourage and require new multidisciplinary research projects beyond the scope
and resources of this article.
Given these premises, it is no surprise that there be speculation and disagreement
among scholars over the botanical identication of ancient Greek hellèboros and its two
varieties, hellèboros mèlas (black hellebore) and hellèboros leukòs (white hellebore). The
Greek hellèboros mèlas has generally been attributed with the modern botanical identica-
tion of Helleborus cyclophyllus, while the ancient hellèboros leukòs is generally identied as
Veratrum album (Aliotta et al., 2002; Totelin, 2009; Hünemörder, 2015; Touwaide, 2015).
These identications are based on morphological similarities between the descriptions in
ancient texts and modern botanically classied specimens: shape, parts of the plant,
arrangement of leaves, color of the stem, leaves, and roots; moreover, these identications
rely on these speciesendemicity to the Balkan macroregion and its microclimates in
modern times.
These identications are indeed backed by authoritative scholarly tradition; yet, our
discussion is raising cautions over their mainstay criteria: morphological identication
and modern oral distribution. Indeed, these identications are not undisputed: scholars
have also proposed identifying ancient references to hellebore with a variety of other
species, belonging mostly to the Ranuculaceae family: Helleborus niger, Helleborus purpur-
ascens, Helleborus viridis, Helleborus orientalis, including the antique classication of
7
On the sources on Theophrastus, see Squillace and Villoresi (2010).
JOURNAL OF THE HISTORY OF THE NEUROSCIENCES 203
Helleborus ocinalis (Sibthorp & Smith, 1825, 19f., 523f.; Thomson, 1835, 810f.; de
Halàcsy, 1900, Girard, 1986; Keyser & Irby-Massie, 2008).
Our team wishes to propose a contribution to this argument by verifying the pharma-
cological properties of these plants and comparing their medical eects with the applica-
tions and circumstances described in ancient sources. Regarding the black hellebore,
associated to the myth of Melampus, we are looking into the chemical characteristics of
three Ranuculaceae: H. cyclophyllus, H. niger, and H. orientalis.
Tests conducted on Helleborus cyclophyllus have evidenced the presence of hellebrin in
its constituents: This substance makes the plant highly cardiotoxic and cytotoxic (anti-
neoplastic). H. cyclophyllus also contains high levels of 20-hydroxyecdysone and 5β,20-
dihydroxyecdysone, providing a potent anti-inammatory action. The structure of helleb-
rin has been studied and perfected (Karrer, 1943; Schmutz, 1949). Hellebrin represents a
typical bufadienolide cardiac glycoside, the 3-β-O-[4-O-(β-D-glucopyranosyl)-α-L-rham-
nopyranosyl]hellebrigenin (Muhr et al., 1995) with extraordinarily high in vivo (cardio)
toxicity (lethal dose [LD] 100% in cats: LD
100
= 0.1040 ± 0.0030 mg) (Schmutz, 1949).
Additionally, hellebrin exhibits nanomolar cytotoxic properties and, therefore, is under
consideration as an antineoplastic agent (Lindholm et al., 2002; Moreno et al., 2013).
Tests conducted on Helleborus niger reveal that this species, unlike H. cyclophyllus, does
not contain hellebrin, making H. niger far less toxic.
8
Similarly to H. cyclophyllus, H. niger
also contains 20-hydroxyecdysone and protoanemonin: this provides H. niger with anti-
inammatory properties though less potent than H. cyclophyllus, which contains also
5β,20-dihydroxyecdysone. H. niger contains unique hellebosaponins: these compounds
have purgative and cathartic eects and, moreover, hellebosaponins have a hypnotic eect.
H. niger has proven to contain also sarsasapogenins: these compounds have antidepressant
and antipsychotic properties. Therefore, the hellebosaponins and sarsasapogenins in
Helleborus niger seem to substantiate two of the main applications of hellebore in ancient
sources: the purgative and psychoactive properties.
Helleborus orientalis seems to have the dangerous toxicity of H. cyclophyllus and none
of the interesting medical properties of H. niger. This species not only contains the toxic
hellebrin but also high levels of desglucohellebrin (0.5%), making it cytotoxic (antineo-
plastic) and highly cardiotoxic. The hellebosaponins, common to the Helleborus genus,
provide it with emetic and laxative (purgative) eects. Lacking traces of sarsasapogenin
saponins, this plant has no proven antispychotic and/or antidepressant properties.
All of these Helleborus species are toxic to some degree: This would explain the overall
caution that ancient sources called for in both gathering and administering hellebore and
the potent and debilitating eects the hellebore drugs were generally known to produce.
How can these pharmacological properties be related to the historical contextua-
lization of hellebore that we have provided in this article? As we have outlined,
hellebore drugs were associated with dierent medical eects: purgative,
8
The presence of hellebrin in Helleborus niger has been claimed by W. Karrer (1943), but more recent
investigations have clearly excluded the presence of hellebrin in Helleborus niger (Wissner & Kating,
1974; Liedtke et al., 1997): it is likely that W. Karrer isolated hellebrin from the species Helleborus
purpurascens, mistaking it for Helleborus niger.
204 M. F. OLIVIERI ET AL.
antipsychotic, and hypnotic but also toxic, noxious, or lethal. Ancient texts illustrate
abaing diversity of hellebore medical preparations and uses
9
: The potency of the
drugs diers from source to source and is varyingly put into relation as to the mode
of preparation, admixture, provenance of the specimens, parts of the plant employed
or to be avoided mode of administration. This confusion may explain the
counterindications, the ill eects, and even the deaths related to the medical uses of
hellebore in some of the ancient texts (Girard, 1986, pp. 98102).
We believe that the multifarious and contradictory nature of our ancient sources can be
understood in light of the pharmacological data we have gathered: specic outcomes of
administration can be attributed to specic botanical species or varieties of Helleborus.
Needless to say, this requires refocusing research on ancient hellebore on the basis of case
studies: outlining and analyzing the historical circumstances, patients, symptomatology,
diagnosis, and medical eects for each specic case or group of cases. In other words, we
should not seek to establish any one correctunequivocal match between ancient
hellebore tout court and one single botanical species. If we waive establishing an unequi-
vocal identication and if we accept the diversity of ancient applications and eects, it
becomes more reasonable we think to reconstruct that, in antiquity, under the
common label of hellèboros and helleborus (respectively in Greek and Latin) and under the
labels of black and white hellebore, a whole assortment of dierent botanical species and
varieties (perhaps but not necessarily phytogenetically or morphologically related)
circulated in the herbal markets.
A good deal of scholarship has preferred to identify Helleborus cyclophyllus as the
scientic botanical correspondent of the ancient Greek hellèboros mèlas. But the pharma-
cological analysis shows that this species is considerably more toxic than Helleborus niger
because of its cytotoxic properties (Lindholm et al., 2002; Moreno et al., 2013). Hence, H.
cyclophyllus can certainly be taken as a valid identication in those sources that remark on
the debilitating eects of the drugs. For instance, this might be the case of Mnesitheos of
Cyzicus, in the second-century BC, who eschewed hellebore altogether as too dangerous
(Keyser & Irby-Massie, 2008, p. 561).
Pharmacological analysis shows that Helleborus niger has a lower toxicity and more
noteworthy neurological properties than H. cyclophyllus: therefore, we propose to take into
consideration Helleborus niger as the referent for black hellebore,specically for those
narratives in which the plant or the remedy were praised for their favorable qualities. The
special psychoactive properties that have emerged from the pharmacological tests on
Helleborus niger encourage looking to this species in those circumstances in which
Greek and Roman physicians prescribed hellebore for curing madness and mental
conditions.
Reference literature on Helleborus niger (Ren et al., 2006,2007) proves an in vivo
antidepressant eect of sarsasapogenin contained in the Helleborus niger leaf and stem as
glycosylated saponin (see Fig. 3 and 4,Table 1; Karle & Karle, 1966; Linde et al., 1971;
Mariezcurrena et al., 1972; Martinek, 1973,1974; Canonica et al., 1974; Bonora et al., 1987;
Liedtke et al., 1997; Mimaki et al., 2003; Vitalini, Braca, & Fico, 2011; Duckstein et al.,
9
For instance, Theophrastus (Historia Plantarum, 9.17.23) reported that the same drug showed
opposite potency when taken by two medics: Eudemos of Athens who could not withstand the
eect and Eunomos of Chios who took much with impunity.
JOURNAL OF THE HISTORY OF THE NEUROSCIENCES 205
2014; Duckstein & Stintzing 2014). Sarsasapogenin performed equally to the reference
selective serotonin re-uptake inhibitor (SSRI) drug uoxetine in vivo (Ren et al., 2006,
2007). The concentrations of the monoamine neurotransmitters serotonin, noradrenaline
(norepinephrine), and dopamine were increased by sarsasapogenin treatment in mouse
brain hypothalamus and hippocampus, comparable in eect to the in vivo treatment with
uoxetine (Ren et al., 2006). Moreover, sarsasapogenin showed monoamine oxidase A
(MAO-A) and B (MAO-B) inhibitory action in mouse brains, whereas the control drug
uoxetine did not (Ren et al., 2006).
The legend that links the use of hellebore in curing the Proetidesmadness to the
plants digestion by a ock of goats provides a tantalizing suggestion to this pharmaco-
logical analysis (Pliny, Natural History, 25.21.47). Saponins from Helleborus niger can act
as antidepressant medication when the plant is digested by ruminants. When animals
graze on helleborus leafs and stems, the carbohydrates are split from the saponin aglycons
(sapogenins) (Wang & McAllister, 2010) in the ruminantsredigesting stomach (rumen).
Therefore, since these sapogenins are highly lipophilic, they concentrate in the animals
milk. So in the myth of the shepherd Melampus, the therapeutic agents, sapogenins, would
have been concentrated in the goatsmilk and would in fact have neuropharmacologic
action. Although Helleborus sapogenins dier in chemical structure from classical (psy-
cho)pharmacological agents like benzodiazepines, they may nevertheless prove to be of
(psycho)therapeutic value. Alternatively, Helleborus niger leaf and stem could also exhibit
direct pharmacological eects without Helleborus saponin rumen deglycosylation and
saponin aglycon accumulation in the ruminantsmilk. The phytoecdysteroid 20-hydro-
xyecdysone (β-ecdysone, ecdysterone) (Fig. 4,Table 1) showed anti-inammatory action
Figure 3. Photograph of Helleborus niger L. ssp. niger (Ranunculaceae). Courtesy and copyright of
Andreas J. Kesel.
206 M. F. OLIVIERI ET AL.
Figure 4. Proven constituents of Helleborus niger L. ssp. niger (Ranunculaceae) with indicated plant organ distribution.
JOURNAL OF THE HISTORY OF THE NEUROSCIENCES 207
Table 1. Proven constituents of Helleborus niger L. ssp. niger (Ranunculaceae).
H. niger L. ssp. niger Natural
Product Constituent(s)
Natural Product
Class
Found in H. niger
L. ssp. niger Plant
Organ
Metabolite(s) Presumably
Concentrated in Ruminants
(Cow, Goat) Milk After Their
Grazing on H. niger L. ssp.
niger Plant ReferencesLeaf Stem Root
Phenylpropanoids
3-Phenyllactic acid 2-O-β-D-
glucoside
× × 3-Phenyllactic acid and/or (E)-
cinnamic acid
Vitalini, Braca, &
Fico, 2011;
Duckstein &
Stintzing, 2014
Ester O-glycosides of caeic
acid, ferulic acid and
p-coumaric acid
×× Caeic acid, ferulic acid and
p-coumaric acid
Duckstein &
Stintzing, 2014
γ-Lactones
Ranunculin and
protoanemonin
× × Protoanemonin, anemonin Duckstein &
Stintzing, 2014;
Bonora et al.,
1987; Karle &
Karle, 1966
Ranuncoside × × 5-Hydroxylevulinic acid and/
or its ketal dimer
Martinek, 1973,
1974;
Mariezcurrena
et al., 1972
Flavonoid
glycosides
Kaempferol 3-O-[2-O-(α-L-
arabinopyranosyl)-β-D-
galactopyranoside] 7-O-β-
D-glucopyranoside
×Vitalini, Braca, &
Fico, 2011;
Duckstein &
Stintzing, 2014
Quercetin 3-O-{2-O-[2-O-(E)-
caeoyl-α-L-
arabinopyranosyl]-β-D-
glucopyranoside} 7-O-β-D-
glucopyranoside
×× Vitalini, Braca, &
Fico, 2011;
Duckstein &
Stintzing, 2014
Ecdysteroids
(insect ecdysis/
molting
hormones)
β-Ecdysone (ecdysterone, 20-
hydroxyecdysone)
× × × Poststerone, rubrosterone
and other microbiological
metabolites
Duckstein &
Stintzing, 2014;
Liedtke et al.,
1997; Canonica
et al., 1974
Steroidal
saponins
Macranthoside I × × × Macranthogenin [5β-spirost-
25(27)-ene-3β-ol]
Duckstein &
Stintzing, 2014;
Liedtke et al.,
1997
Hellebosaponin A and D × Spirosta-5,25(27)-diene-
1β,3β,21,23α,24α-pentol
Duckstein et al.,
2014; Mimaki
et al., 2003
Saponins with spirosta-5,25
(27)-diene-1β,3β,11α-triol
as sapogenin
× Spirosta-5,25(27)-diene-
1β,3β,11α-triol
Linde et al.,
1971
Saponins with
sarsasapogenin as
sapogenin
× × Sarsasapogenin [(25S)-5β-
spirostan-3β-ol]
Duckstein &
Stintzing, 2014
208 M. F. OLIVIERI ET AL.
by inhibiting nuclear factor-kappa B (NF-κB)-mediated, cyclooxygenase (COX)-2 (indu-
cible COX, COX-2)-mediated (Zhang et al., 2014), and nitric oxide (N=O)-mediated (Lee
et al., 2012)inammation. Moreover, 20-hydroxyecdysone inhibited matrix metallopro-
teinase 3 (Lee et al., 2012; Zhang et al., 2014), an enzyme involved in the development and
spread of inammation. Anemonin, the [2π+2π]-cycloaddition dimer of protoanemonin,
was an eective inhibitor of inducible nitric oxide synthase (iNOS, NOS-2), an important
enzyme contributing to the genesis of inammation (Duan et al., 2006; Lee et al., 2008;Hu
et al., 2009). In addition, anemonin inhibited endothelin-1 (ET-1; Duan et al., 2006; Lee
et al., 2008; Hu et al., 2009), intercellular adhesion molecule-1 (ICAM-1; Duan et al.,
2006), tumor necrosis factor-α(TNF-α; Hu et al., 2009) and interleukin-1α(IL-1α)
expression (Hu et al., 2009) induced by lipopolysaccharide (LPS). These latter factors
are all important generators of inammation.
In conclusion, Helleborus niger thus seems to be a tting explanation for the medical and
neurological eects that have been identied in the case study of the myth of the healing of the
Proetidesmadness: the sedative and hypnotic eect of the Helleborus species (H. cyclophyllus
or H. niger) but especially the antidepressant action of the Helleborus niger point to these
conclusions. Moreover, ancient Greek medical sources (especially the Hippocratic ones)
mention hellebore in a number of gynecological remedies: also, in this case, conclusions
point to the anti-inammatory action for dysmenorrhea unique to H. niger.
Conclusions: Myths, history, and science in ancient neuroscience
This research has tackled a relatively familiar myth of ancient Greek medicine, but it has
done so proceeding by multidisciplinary methodology with the intent of providing
innovative insight into cultural and scientic aspects of early Greek pharmacology and
psychiatry. The historical contextualization of the myth of the healing of the Proetides
madness provided our team with the basis to investigate ancient neuroscience: we have
looked into the signicance of the gure of Melampus for the early history of Greek
neuroscience, the receptivity of ancient medical thought towards psychology and psychia-
try, and the history and identication of the pharmacological use of Helleborus niger as a
psychoactive medicament.
Greek myths placed Melampus at the dawn of ancient medical practice. Even in the
nonmedical legends on Melampus, we may trace conceptual associations to the etiology and
sphere of Greek medicine. Melampusprophetic skills were attributed to a connection to a
higher power (Buxton, 2010): the god Dionysus or Apollo depending on the versions of the
myth. Now, Apollo is the god among other spheres of life of oracular prophecy, and he
also had the attribute of inicting diseases and curing them (Burkert, 1987). Snakes play a
signicant etiological role in Melampusacquisition of his foresight (manti) (Bremmer,
2015): the association of these animals to medicine and its symbology is renown (Wilcox &
Whitham, 2003), beginning from their association with the god Asclepius, born of Apollo.
The association between Melampus and medicine makes this gure a sort of proxy to
reconsider the mental framework of the earliest phases of Greek medical thought. The skills
and semantic associations attached to Melampus place him broadly within the spheres of
prophecy, disease, and healing: indeed, Melampus came to be considered as the archetypal
iatromantis,thehealing seer(Suárez de la Torre, 1992;Holmes,2010). This conrms the
association between the spheres of the supernatural and the medical in early Greek thought.
JOURNAL OF THE HISTORY OF THE NEUROSCIENCES 209
Our research has reviewed the conception of mental disease in early Greek sources and we
have remarked on the blurring of the divide between the theologicaland medicalizedin
early Greek medicine. We should indeed remark on the speciousness of considering the two
approaches anything but parallel throughout Greco-Roman culture. In the archaic period
(eighth to sixth centuries BC), thinkers who were variously addressed as seers,”“healers,
iatromanteis,or sophoi(wise men; see Herodotus, 2.49.2) were men of special intellec-
tual prowess, capable of providing society with solutions for issues in a broad range: political
decisions, social organization, norms of conduct, moral rectitude, psychological unrest,
mental and physical healing, and the unexplained (Flower, 2008). Such a holistic and
only apparently contradictory competency belongs to an age in the history of sciences when
disciplines had not yet been conceptualized, categorized or sectorialized (Mosshammer, 1976;
Iles Johnston, 2008; Christes, 2010).
With these premises, we believe that the iatromantis (seer-healer) would likely have
been considered the person most capable of identifying, diagnosing, and healing disorders
of the psyche due to this specialists holistic skills in matters of man and society and of his
privileged relationship with the world of the unseen (Holmes, 2010, pp. 8184). In this
perspective, the historical contextualization of the legends on Melampus contribute to
outlining some of the deeper roots of the medicalizing shiftin Greek thought, tracing
them back to the traditional practices of the archaic iatromanteis (seer-healers).
Our analysis of the sources on Melampus and the Proetides has brought to light
medicalizedfeatures in the descriptions of madness, both in medically oriented
sources as well as in earlier legendary narratives. This observation ts the conclusions
of the retrospective diagnosis we have proposed, which has attempted to substantiate
the recurrent features of madnessas described in ancient sources with understand-
able categories. Our conclusions have suggested recognizing in the Greco-Roman
culture, even in earliest Greek sources, a degree of awareness with respect to mental
conditions and an early articulation albeit intuitive of psychiatry, an interest
towards understanding causes and mechanisms, even the search for proper and specic
cures. Furthermore, some authors highlight the fact that Proetusdaughters went mad
when they reached the age of marriage (Apollodorus, Library, 2.2.2) or got married just
after being healed from madness (Pherekydes, FGrH,3fr.114).Now,historicaland
literary studies rather safely have estimated the age of marriage of girls in ancient
Greece at 1418 years of age (Ingall, 2001). Hence, we should speak not merely of a
concern for psychological conditions but of a specic awareness of the psychology of
one particular social group of a specic age and sex and of the specic forms of
disorders from which young women might suer. This is conrmed, for instance, by
the Hippocratic treaty focusing On the Diseases of Virgins.
Not only may we recognize early traces of the awareness of mental conditions in
antiquity but also the research on the use of hellebore and on its role in these legends
suggests new insight into the early history of pharmacological cures for mental
conditions. We have brought to light an apparently widespread, longstanding, and
populartraditionconcerningthemedicaluseandtheknowledgeofthepsychoactive
action of hellebore in ancient Greek culture.Wehavecombineddatafromhistorical,
psychological, and pharmacological methodologies. Our outcome is to propose here a
less orthodox identication of ancient Greek Hellèboros mèlas with the botanical
specimen Helleborus niger: we argue that this species more closely matches the
210 M. F. OLIVIERI ET AL.
medicinal eects attributed to hellebore in a certain group of sources, including those
on the Proetides and Melampus. We believe Helleborus niger should be taken into
serious consideration in the cases in which hellebore was described to have psychoac-
tive action: calming, antipsychotic, and antidepressant eects.
We would like to conclude with a cautious and yet methodologically constructive
remark. Melampus, the Proetides, the healing processes using the psychoactive substance
hellebore, notwithstanding our discussion, remain myths and are not historical personages
nor actual events. W. Burkert denes mythas a traditional tale with a reference to
something of collective importance.Therefore, we can indeed we must ground our
research on ancient myths within the scope of extracting the knowledge they can provide
about the society, culture, and historical contexts in which they were set down and
transmitted (Burkert, 1979, pp. 2226). We look thus not to the historicity of myth but
rather to its historical value. Pursuing Greek and Roman myths by innovative approaches,
we may dare pose new questions about the identication and discussion of the early steps
of ancient Greek psychiatry, pharmacology, and neuroscience.
Acknowledgment
The authors thank Mrs. Patricia Ann Sawchuck for revising and proofreading the language and
syntax of the article.
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... O dönemde psikiyatrik hastalıklar tanımlanmadığı için hastalıkların ne olduğu teşhis edilemese de, bugün kızların psikosomatik bir cilt hastalığı olduğu ve hekim tarafından yapılanların da psikosomatik müdahale olduğu düşünülmektedir. 9,13 Argos'un kızları iyileşse de o dönemde Eski Yunanlılarda benzer müdahalelere maruz kalan birçok psikiyatri hastasının öldüğü ve zarar vermeme ilkesinin ihlal edildiği bilinmektedir. 1,11 İlerleyen yıllarda dinin etkisi ile hastalıkların tedavilerinde bu tür uygulamalara yer verilmemiştir. ...
... 1,11 İlerleyen yıllarda dinin etkisi ile hastalıkların tedavilerinde bu tür uygulamalara yer verilmemiştir. 13 Hippokrates düşleri yorumlamaya çalışmış ve "Düşe Dair" adlı kitabında psikanalize yakın açıklamalar yaptığı görülmüştür. Euriphon'un aksine tedavi etmeyi değil, hastalıkların nedenini anlamaya odaklanarak ruhsal hastalıkların kökenini saptamaya çalışmıştır. ...
... The popular use of black hellebore as a treatment for epilepsy is also evident in Greek myths that share one common characteristic: the treatment of sudden outbursts of "madness". In the myth of Melampus, a famous clairvoyant and healer, black hellebore was used to cure the daughters of King Proteus who were stricken by divine "madness" and wandered in the wild believing they were cows (Olivieri et al., 2017). In the myth of Heracles, the famous hellebore from Antikyra healed Heracles of the "madness" caused by Hera who drove him to kill his wife and children. ...
... More recently, the pharmacological effects of Helleborus species included anti-rheumatic, anti-inflammatory, anti-cancer, anti-diabetic, anti-bacterial, and antioxidant properties (Apetrei et al., 2011;Erdemoglu et al., 2003;Lindholm et al., 2002;Puglisi et al., 2009;Seifarth et al., 2011). In addition, the CNS antidepressant effect has been linked to saponins (sarsasapogenin and its glycosylated form) contained in H. niger (Olivieri et al., 2017;Ren et al., 2007). Nevertheless, all the abovementioned pharmacological properties of hellebore are overshadowed by the high cardiotoxic and cytotoxic properties of most species (Gomes et al., 2009;Moreno et al., 2013;Schmutz, 1949), whose dangerous results have been known since antiquity. ...
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Ethnopharmacological relevance Ethnopharmacological data and ancient texts support the use of black hellebore (Helleborus odorus subsp. cyclophyllus, Ranunculaceae) for the management and treatment of epilepsy in ancient Greece. Aim of the study A pharmacological investigation of the root methanolic extract (RME) was conducted using the zebrafish epilepsy model to isolate and identify the compounds responsible for a potential antiseizure activity and to provide evidence of its historical use. In addition, a comprehensive metabolite profiling of this studied species was proposed. Materials and methods The roots were extracted by solvents of increasing polarity and root decoction (RDE) was also prepared. The extracts were evaluated for antiseizure activity using a larval zebrafish epilepsy model with pentylenetetrazole (PTZ)-induced seizures. The RME exhibited the highest antiseizure activity and was therefore selected for bioactivity-guided fractionation. Isolated compounds were fully characterized by NMR and high-resolution tandem mass spectrometry (HRMS/MS). The UHPLC-HRMS/MS analyses of the RME and RDE were used for dereplication and metabolite profiling. Results The RME showed 80% inhibition of PTZ-induced locomotor activity (300 μg/ml). This extract was fractionated and resulted in the isolation of a new glucopyranosyl-deoxyribonolactone (1) and a new furostanol saponin derivative (2), as well as 20-hydroxyecdysone (3), hellebrin (4), a spirostanol glycoside derivative (5) and deglucohellebrin (6). The antiseizure activity of RME was found to be due to the new furostanol saponin (2), hellebrin (4), which reduced 45% and 60% of PTZ-induced seizures (135 μM, respectively). Besides, the aglycone of hellebrin, hellebrigenin (S34), was also active (45% at 7 μM). To further characterize the chemical composition of both RME and RDE, 30 compounds (A7-33, A35–37) were annotated based on UHPLC-HRMS/MS metabolite profiling. This revealed the presence of additional bufadienolides, furostanols and evidenced alkaloids. Conclusions This study is the first to identify the molecular basis of the ethnopharmacological use of black hellebore for the treatment of epilepsy. This was achieved using a microscale zebrafish epilepsy model to rapidly quantify in vivo antiseizure activity. The UHPLC-HRMS/MS profile revealed the chemical diversity of the extracts and the presence of numerous bufadienolides, furostanols and ecdysteroids, also present in the decoction.
... In literature an impressive number of information is reported about the plants employed to treat symptoms related to the most common psychiatric disorders [93,94]. Among these, it is noteworthy to mention the mandrake, whose magical qualities were showed during the Middle ages, probably for its sedativehypnotics effects or the hellebore, a drug known to treat paranoia, epilepsy [92,95], and also hysterical suffocation which today refers to "functional neurologic symptom disorder" [96]. In this context, it is remarkable to mention the important traditional drugs extracted from plants, able to affect the central nervous system (CNS). ...
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... In this regard, the Moomiaii is a unique and renowned compound that commonly used in TM systems. This compound, also known as Shilajit, Silajita, Marathi or Gujarati (in Hindi), Asphalt (in English), Silajatu (in Bengali), Rock juice (in Tibet), Conqueror of mountains (in Sanskrit), Hajarul-Musa or Araq-al-jibal (in Arabic), Moomiaii or Mumnaei (in Persian), μούμια (in Greek), Myemu (in Russian), Mumie (in German), Mineral Pitch, Jew's Pitch, Mineral Wax, and Bragshun, as a pale-brown to blackish-brown natural substance has been used over 3000 years as a rejuvenator, adaptogen compound ( Figure-1 A) [4]. The Moomiaii is formed in very small quantities in some specific weather conditions and obtained from steep rocks at high altitudes when it becoming less viscous and extruded from the layers of these rocks during summertime [5]. ...
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