SOME HISTORY AND EFFECTS OF

CONIUM MACULATUM L.

by Thomas Larsson,
a literature work in Pharmacognosy C,
Department of Medicinal chemistry,
Uppsala University, 2004.
Supervisor: Lars Bohlin.

Larsson | Some history and effects of Conium maculatum L.

Cover: The Death of Socrates by Jacques-Louis David, 1787, Metropolitan Museum of Art, New
York. Source: http://www.ibiblio.org/wm/paint/auth/david/socrates.jpg

1. Abbreviations
BBB
C(integer), e.g. C(5)
C-integer, e.g. C-5
14
C
CNS
E

et al.
IM
SARs

blood brain barrier

the number of carbon atoms in an organic
compound
a specific carbon atom in an organic compound
carbon-14, a radioactive isomer to the common
carbon-12
central nervous system
from German Entegen, which means opposite.
Through
the
Cahn-Ingold-Prelog-rules
the
functional groups around a double bond are valued,
and if high priority groups through a number of
sequences are on opposite sides, the compound are
named E-... If they are on the same side it is called
Z, which means Zuzammen, meaning together.
et alii, and others
intramuscular injection
structure-activity relationships

2. Wordlist
The word in question will not be included in the list, if it is written only once and
described in the text. If it can be visualized, e.g. hypersalivation (hyper: over,
exaggerated plus salivation), it will not be included either. If the word is
underlined in the text it means that one can find it in this list.
agonal
amniotic fluid
anodyne
arthrogryposis
asphyctic

describing or relating to the phenomena that are

associated with the moment of death
the fluid contained within the amniotic cavity. It
surrounds the growing fetus, protecting it from external
pressure.
pain-relieving, analgesic agent
contracture of soft tissues that causes fixed deformities
of the joints if untreated.
condition of asphyxia; suffocation, a life-threatening
state in which oxygen is prevented from reaching the
tissues by damage to any part of the respiratory system.
ataxia the shaky movements and unsteady gait that
result from the brains failure to regulate the bodys
posture and the strength and direction of limb
movements. It may be due to disease of the sensory
nerves or the cerebellum.

Larsson | Some history and effects of Conium maculatum L.

biopsy
biotransformation
carpal
chorea

cleft palate
clonic

clonus

congenital

cyanosis
cyanotic
depressor
diurnal
encephalopathy
etiology
extensor
fasciculation
gestation
gout
histological

the removal of a small piece of living tissue from an

organ or part of the body for microscopic examination.
the changes of chemical compounds that occur in the
body
relating to the wrist
jerky involuntary movement particularly affecting the
head, face or limbs. Each movement is sudden, but the
resulting posture may be prolonged for a few seconds.
cleft palate fissure in the midline of the palate due to
failure of the two sides to fuse in embryonic
development. Only part of the palate may be affected,
or the cleft may extend the full length with bilateral
clefts at the front of the upper jaw.
a fissure in the midline of the palate due to failure of the
two sides to fuse in embryonic development.
relating to, or resembling clonus. The term is most
commonly used to describe the rythmical limb
movements seen as a part of a convulsive
epileptic seizure.
rythmical contraction of a muscle in response to a
suddenly applied and then sustained stretch stimulus. It
is caused by an exaggeration of the stretch reflexes and
is usually a sign of disease in the brain or spinal
cord.
describing a condition that is recognized at birth or that
is believed to have been present since birth. Congenital
malformations include all disorders present at birth
whether they are inherited or caused by an
environmental factor.
a bluish discoloration of the skin and mucous
membranes resulting from an inadequate amount of
oxygen in the blood.
the condition of cyanosis.
here; a nerve that lowers blood pressure.
daily
any of various diseases that affect the functioning of the
brain.
1. the study or science of the causes of a disease. 2. the
cause of a specific disease.
any muscle that causes the straightening of a limb or
other part.
brief spontaneous contraction of a few muscle fibers,
which is seen as a flicker of movement under the skin.
pregnancy among animals and humans.
a disease in which a defect in uric acid metabolism
causes an excess of the acid and its salts (urates) to
accumulate in the blood-stream and in the joints.
referring to histology

Larsson | Some history and effects of Conium maculatum L.

histology
hypermetria
in utero
joint

lateral
lead compound

lethargy
mandibular
mandible
mericarp
metacarpophalangic
joints
myoglobinuria
nictitating
membranes
palate
patellar reflex

phrenic nerve

placentation
polyphagous
postnatal
postpartum

the study of the structure of tissues by means of special

staining techniques combined with light and electron
microscopy.
a condition in which voluntarily muscular movement
overreaches the intended goal
inside the uterus
the point at which two or more bones are connected.
The opposing surfaces of the bones are lined with
cartilaginous, fibrous or soft tissue knee-jerk see
patellar reflex
here: situated at or related to the side of an organ or
organism.
the starting compound in the development of a novel
drug. Often the lead compound can have serious side
effects, be expensive to synthetize etc., but it always
have some sort of desired effect worth studying.
mental and physical sluggishness: a degree of inactivity
and an unresponsiveness approaching. The condition
results from disease or hypnosis.
reffering to mandible
the lower jawbone. It consists of a horseshoe-shaped
body, the upper surface of which bears the lower teeth,
and two vertical parts (rami).
a part of the fruit
the area where the part of the hand with its five
cylindrical bones and wrist meet
or myohemoglobinuria; the presence of the pigment
myohemoglobin in the urine.
blink membranes
the roof of the mouth, which separates the mouth from
the nasal cavity
the knee jerk, in which stretching the muscle at the
front of the thigh by tapping its tendon below the knee
cap causes a reflex contraction of the muscle, so that
the leg kicks.
the nerve that supplies the muscles of the diaphragm.
On each side it arises in the neck from the third, fourth
and fifth cervical spinal roots and passes downward
between the lungs and the heart to reach the diaphragm.
Impulses through the nerves from the brain bring about
the regular contractions of the diaphragm during
breathing.
the manner of ovule attachment within the ovary; the
process of placenta formation.
describing an animal that consumes a wide selection of
food
after birth
relating to the period of a few days immediately after
birth

Larsson | Some history and effects of Conium maculatum L.

prenatal
pressor effect
recumbency
rhabdomyolysis
scoliosis

sequela
sequelae
teratogenic
tonic
torticollis
vasoconstriction

vasomotor center

before birth
an agent that raises blood pressure.
lying down
disintegration or dissolution of muscle, associated with
excretion of myoglobin in the urine
lateral (sideway) deviation of the backbone, caused by
congenital or acquired abnormalities of the vertebrae,
mucles and nerves.Treatment is with spinal braces, and
in cases of severe deformity, surgical correction
by fusion or osteotomy is done.
any disorder or pathological condition that results from
a preceeding disease or accident.
plural form of sequela
adjective of teratogen, any substance, agent or process
that induces the formation of developmental
abnormalities in a fetus.
here: marked by continuous tension (contraction).
wryneck; an irresistable turning movement of the head
that becomes more persistent, so that eventually the
head is held continually to one side.
a decrease in the diameter of the blood vessels,
especially arteries. This results from activation of the
vasomotor center in the brain, which brings
about contraction of the muscular walls of the arteries
and hence an increase in blood pressure.
a collection of nerve cells in the medulla oblongata that
receives information from sensory receptors in the
circulatory system, and brings about reflex changes in
the rate of heartbeat and in the diameter of blood
vessels, so that blood pressure can be adjusted. The
vasomotor center also receives impulses from
elsewhere in the brain, so that emotion (such as fear)
may also influence the heart rate and blood pressure.
The center works through vasomotor nerves of the
sympathetic and parasympathetic systems.

Sources: The Bantam Medical Dictionary, 2000; Biology of Plants, Raven et al.,
1992; International Dictionary of Medicine and Biology Vol 1 and 3, 1986;
Dorlands Illustrated Medical Dictionary, 2000.

3. Introduction
Conium maculatum (hemlock, poison hemlock) is a very common and worldwide
plant species. It is one of the most toxic plants known [Vetter, 2004]. Poison
hemlock is native to Europe and western Asia and has been brought in America
and Oceania as an ornamental plant [Lpez et al., 1999 (1)], although in other
countries, for example Norway the plant have been introduced through the
transport of grain [Vetter, 2004 (2)].

Larsson | Some history and effects of Conium maculatum L.

The old Roman name of C. maculatum was Cicuta, but this name was later
occupied to another near related umbelliferous plant, Cicuta virosa L., (water
hemlock) by Gesner, 1541. Then Linnaeus gave its classical Greek name Conium
maculatum. Its generic name was derived from the Greek word Konas, which
means to whirl about, since consumption of the plant causes ataxia, tremor and
convulsions. The specific name (maculatum) is a Latin word, which means
spotted and refers to its very characteristic browninsh-reddish spots of the stem
[Vetter, 2004].
The English name hemlock can be little confusing since there are several different
hemlocks, see chapter 4, Botanical characterization. therefore the Latin name
Conium maculatum will be used mostly throughout this article.
However, water hemlock, Cicuta virosa, is also toxic to animals and humans and
a brief description of this plant and its active substances will be given later in this
text. As with many other toxic plants which cause episodic poisoning incidents,
they biosynthesize and accumulate compounds that provide a protective function
against predation or a competitive advantage relative to other plants and
microorganisms. These bioactive compounds have such serious effects on animals
when consumed; they are also a threat to the livestock producers. This threat has
decreased much the last few decades because of better equipment and techniques
to isolate and identify these compounds. By changing the dose of the bioactive
compound, the effect may be changed and could be manipulated to yield maybe
even beneficial results [James et. al, 2004].
There are many plant genera which contain piperidine alkaloids that fulfill the
teratogenic structural requirements, for example Conium, Nicotiana, Lupinus,
Lobelia, Pinus, Punica, Dubosia, Sedum, Withania, Carica, Hydrangea, Dichroa,
Cassia, Prosopis, Genista, Ammondendron, Liparia, Collidium, and others. Many
of them show structural similarity to known piperidine teratogens, this suggests
that some of the piperidine alkaloids in these plants may be teratogenic [Bunch et
al., 1992 (13)].

4. Botanical characterization
4.1. Physical description, habitats etc.
Conium maculatum L., a member of Apiaceae (formerly Umbelliferae) of
ryzomal plants, the carrot family [Vetter, 2004], is an annual, biennial or in
favourable conditions perennial plant, usually 120-180 cm. high. During the first
year of growth C. maculatum reaches 45 cm height forming dense stands around
the parent plants. The second year new plants grow from rosettes, with larger
leaves which are dark green, bisected, triangular and glabrous [Lpez et al., 1999
(3)]. The root is long, forked, tuberous, pale yellow and reminds about a carrot.
The stem is mottled with irregular purple spots, is erect, bright green and slightly
ridged, much branched above and hollow. The leaves are fern-like [James et al.,
2004], numerous, alternate, long-stalked and tripinnate (which means that they are
divided along the midrib into opposite pairs of leaflets which in turn are divided
and subdivided) [Vetter, 2004]. Its flowers are white, grouped in umbels, which
are small and numerous and have a terminal position, with 12-16 rays per umbel.
It produces a large number of green fruits, 2 to 3 mm long and about 2 mm wide,

Larsson | Some history and effects of Conium maculatum L.

grayish at maturity and formed by two closed mericarps [Lpez et al., 1999 (46)]. The fruit is a broadly ovoid and is composed of two greyish-brown seeds with
five wavy, longitudinal ridges. The petals of the small flowers are white and the
stamens of the flowers are longer than the petals and have white anthers. The
inflorescence is produced mainly from June to September. At germination the
cotyledons are narrow and lanceolate, the first true leaves have two or more
leaflets along an axis and are hairless. The plant has a bitter taste and the odour
reminds about a mouse. Where plants are numerous, the odour can be very
pervasive. The seeds or fruits do not a have very marked odour, but if crushed or
mixed with an alkali as potassium hydroxide solution, the same characteristic,
odour of mouse urine is produced.

Figure 1. Various parts of Conium maculatum L., poison hemlock.

C. maculatum grows in ground, hedgerows, roadsides and woodland, pastures,

banks of streams and rivers, meadows and waste grounds modified soils, along

Larsson | Some history and effects of Conium maculatum L.

fences, roadsides and ditches, around windmills, abandoned constructions and

around woods, under which it can vegetate during the winter [Lpez et al., 1999
(7,8)]. The plant is very common weed in Europe, North and South America,
North Africa, Australia and New Zealand [Vetter, 1999]. C. maculatum is a
nitrophile plant which means that it prefers moist soils with high nitrogen level.
Since it belongs to a group of very common, wide spreaded weed species, its
germination is an important target of investigations. It acts as a pioneer species
which quickly colonize disturbed areas. Poison hemlock can be a persistent weed
species particularly in moist habitats. A single plant may produce 35,000-40,000
seeds, which usually fall near the parent plant, but can be spread by water and
animals [Vetter, 2004 (9)].
Table 1. Non-quantitative comparisons of alkaloid contents in different plant organs of
Conium maculatum. Source: Lpez et al., 1999.
Organs
Fully formed fruit, still green > young leaves > roots
Half-ripe fruits > ripe fruits >> roots
Green fruits > ripe fruits
Stems > leaves > fruits > roots
Stems > leaves >> fruits > roots

Because of the large seed production, it may dominate small areas with a high
density of plants and encroach on alfalfa fields, grass pastures and meadows
(probably because of the rich nitrogen level in these plants). The seeds are nondormant [Lpez et al., 1999 (7,8,10)].
4.2. Other hemlocks and Apiaceaces
It should be noted that water hemlock (Cicuta virosa) is a different yet related
toxic plant that may be more lethal than poison hemlock (C. maculatum). Water
hemlock produces a C(17) polyacetylene neurotoxin termed cicutotoxin which
produces direct brain-neural injury through the induction of convulsions. Since
this group also is poisonous I will touch them briefly here.

Larsson | Some history and effects of Conium maculatum L.

Figure 2. Cicuta virosa L., water hemlock, a near related plant to C. maculatum
Compare with fig. 1.

Eastern hemlock, Tsuga canadensis (L.) Carr, and mountain hemlock, Tsuga
heterophylla, belong to the family Pinaceae, are thereof very distant relatives to
C. maculatum. Clapham et al. stated that there are some 43 genera of Apiaceae
throughout Europe and that these can be grouped into various tribes or subtribes,
depending on their taxonomic similarities. Apiaceae consists of annual or
perennial herbs, rarely shrubs, many of which are strong smelling [Dodds et al.,
1999 (11)].
In an experiment made by Dodds et al., extracts from 33 species representing 32
genera of Apiaceae were screened for antifeedant activity against the field slug,
Deroceras reticulatum, of those 22 triggered nervous activity in the slug ofactory
nerve preparation. Intensity of response differed with plant species, but extracts of
Conium maculatum, Coriandrum sativum (coriander) and Petroselinum crispum
(parsley), seemed to be both the most neuroactive and antifeedant, when
incorporated in a standard food [Dodds et al., 1999]. For a more detailed list of
the 33 species examined, the reader is recommended to see the article of Dodds et

Larsson | Some history and effects of Conium maculatum L.

al., see the reference list. Conium is a close relative to the genus Physospermum,
but the latter was unable to to trigger any activity in the electrophysiological
preparation. A possible explanation for this divergence could be that they are
found in completely different habitats. Conium is living in damp areas such as
open woods or river verges, whereas Physospermum generally grows in grass
verges [Dodds et al., 1999 (11)]. Since mollusks need moist conditions to prevent
desiccation, it seems likely that Conium is more exposed for the slug, which
therefore need some form of defence, in this case antifeedant chemicals released
through the leaves. This study shows, as well as Garraway has stated, that the
most neuroactive extracts were also evidently antifeedants. Electrophysiological
techniques can then give a valuable indication of the antifeedant potential of
naturally occuring substances [Dodds et al., 1999 (12)].

5. The effect in livestock production and other animals

5.1. General
One of the most prevalent economic factors in livestock production is
reproductive efficiency. The most significant are 1) dietary factors essential for
normal reproduction 2) infectious diseases, 3) heredity, 4) management, 5)
environment, and 6) toxic dietary factors. Of those factors mentioned, toxic
dietary factors and natural toxins are these which are least understood and got
least attention, this despite they could be the most important. This picture is
further complicated by the fact that there are many different plants which contains
a range of toxins able to affect reproduction, by that there are many different
mechanisms involved (although only the mechanism of C. maculatum will be
touched here).
The quanities of toxins in the plant varies to a wide degree with environmental
conditions, location and stage of growth. There is a huge variation among the
plants containing these toxins, as well as the plants acceptability as feedstuff for
livestock. Each plant requires in the most cases a special management strategy to
prevent intoxication. Natural toxins are able to affect almost every reproductive
processes.
It have shown through studies the past 40 years that many plants are responsible
for death, abortion or teratogenesis when exposed to livestock. Many of these
malformations have neither been reported nor diagnosed since they have been
ascribed as genetic factors and reduce the importance of environmental causes. It
is now obvious that much of the livestock losses dependent on embryonic death,
abortion and teratogenesis are caused by poisonous plants [Bunch et al., 1992].
Generally one can say that any plant toxin that causes injury to the dam,
particularly in the latter part of the gestation, can cause a small and weak
offspring.
By ultrasound imaging methods Panter et al. have demonstrated some of the
fetotoxic effects of poisonous plants on fetal physiology, growth and development
[James et al., 1992 (14)]. Ingestion of Conium maculatum, Nicotiana glauca and
Lupinus formosus, which contains piperidines, during specific periods of gestation
induced fetal abnormalities (i.e., cleft palate and limb, spine and neck

Larsson | Some history and effects of Conium maculatum L.

contractures). Since the fetus is very dependent on movement in specific periods

during the pregnancy, these plants alkaloids have a severe effect on fetal
movement during critical gestational periods. When feeding of these plants they
are supposed to be responsible for plant-induced cleft palate and skeletal
contractures [James et al., 1992 (15)].
5.2. Sensitivity among the different species
Monogastric animals and ruminants show similar symptoms but different
susceptibilities caused by the ingestion of fresh C. maculatum.
There are cases where domestic animals have ingested C. maculatum despite a
good forage availability [Lpez et al., 1999 (3)]. An apparent willingness to
ingest more hemlock (even if the animal in question have been suffering from
intoxication) has also been recorded for different animal species: cows [Lpez et
al., 1999 (7,8,16), pigs (1,17), goats (18), elk (19) and chickens (20)].

Table 2. The susceptibility among different livestock species

of fresh Conium maculatum. Source: Lopes et al., 1999.
Toxicity

Susceptibility, from highest to lowest

Acute

Cattle > sheep = goats > pigs

Chronic

Cows > sows > sheep

Insects which have been reported to attack C. maculatum are Agonopterix

alstroemeriana (Oecophoridae) [Vetter, 2004 (21)]. Polyphagous lepidopterans,
Eupitheca miserulata, Spilosoma virginica, and others have been notified to eat
the plant. On one polyphagous insect species, Heliothis zea, bioassay for toxicity,
growth inhibition and feeding rejection was done for coniine, but the compound
did not appear to have any biological activity against the insect species at the
concentrations tested [Vetter, 2004 (22)].

6. The substances in hemlock

6.1. General
The majority of the family Apiaceae produce volatile oils in defined tissues
named vittae of the fruits. These tissues also seem to be the sites of synthesis
and/or storage of biologically-active secondary products such as flavonoids and
coumarins [Corsi and Biasci, 1998 (23,24)]. Although Conium maculatum
produces alkaloids, linear furano-coumarins have been isolated from the plant
[Corsi and Biasci, 1998, (25)], and synthesis and/or accumulation sites have not
yet been clearly identified [Corsi and Biasci, 1998 (26,27)]. In a study made by
Corsi and Biasci it was found that all tissues of C. maculatum were very rich in
alkaloids [Corsi and Biasci, 1998]. Cromwell stated that alkaloid synthesis in
Conium maculatum took place more readily in tissues of the shoot than the root
[Corsi and Biasci, 1998, (26)].

Larsson | Some history and effects of Conium maculatum L.

6.2. The alkaloids in Conium maculatum.

There are eight known piperidinic alkaloids in poisonous hemlock [Lpez et al.,
1999, (28, Panter et al., 1988b)]. Two of them, coniine and -coniceine (figure 7
resp. 8) are frequently found in largets amounts. Coniine is reported to be eight
times more toxic than -coniceine [Lpez et al., 1999, (29, The Merck Index,
1996)].

Figure 3. Coniine
(2-propylpiperidine)

Figure 4. Coniceine
(2n-propyl-1-piperidine)

OH
Figure 5. N-methylconiine
(1-methyl-2-propylpiperidine)

Figure 6. Conhydrine
(2-(1-hydroxypropyl)-piperidine)

HO
N

Figure 7. Pseudoconhydrine
((5-hydroxypropyl)-piperidine)

Figure 8. Conhydrinone
((1-oxo-propyl)-piperidine)

HO
N

N
Figure 9. N-methylpseudoconhydrine
((5-hydroxy-1-methyl-2-propyl)-piperidine)

Figure 10. 2-methylpiperidine

O
O
HOOC

Figure 11. Poly--keto acid

(2,5,7-tri-oxo-octanoic acid)

A large width in the outcome regarding the alkaloid content, both qualitatively
and quantitatively have been found, depending on different researchers have not
used exactly the same method, which stage one study and which organ. Other

Larsson | Some history and effects of Conium maculatum L.

parameters which had an effect on the alkaloid concentration was rain (give an
increase of -coniceine level in fruits and flowers) and temperature [Lpez et al.,
1999 (27,30)]; even the diurnal concentration varied in the alkaloids [Lpez et al.,
1999 (17)]. The quantity of alkaloid were the twice during the sunny seasons
compared to cloudy seasons. As the fruits ripen, the alkaloid content increase, and
this also depends upon the soil moisture and its exposure to the sun. Since green
fruits contains more alkaloids than mature fruits and seeds, the level of alkaloids
in fruits reaches its peak while ripening, but reduces near maturity. The
concentrations of coniine and coniceine are found in similar degrees in cloudy
summers, while coniine is most prevalent during dry summers (27). Lpez et al.
have detected a significant increase in the alkaloid concentration of C. maculatum
on nitrogen fertilized soils [Lpez et al., 1999].
Experiments made by Leete has demonstrated that coniine is derived from acetic
acid [Lpez et al., 1999 (31)] by labelling the 1-C atom with the 14C isotope. This
result indicated that coniine is formed from an eight-carbon poly--keto acid (see
Fig. 11), produced by the combination of four acetate units. Obviously is coniceine a precursor of coniine and the other hemlock substances, but the
knowledge of the eight-carbon compound which is converted to the former
alkaloid is still like a black box [Vetter, 2004].
6.3. The polyacetylenes of Cicuta virosa

OH

OH
Figure 12. Cicutoxin, the main substance in Cicuta virosa (water hemlock)
( 8,10,12-Heptadec-triene-4,6-diyne-1,14-diol).

The major toxic substance of water hemlock (Cicuta virosa L.), is cicutoxin,
which belongs to a class of conjugated polyacetlylenes. It is assumed to be
produced from oleic acid in the biotransformation pathway which involves
oxidation and decarboxylation reactions [Uwai et al., 2000 (32)]. The citutoxin
contains the following functional groups: (i) a hydroxyl group and an allylic
hydroxyl group at C-1 and C-14, respectively, (ii) a diacetylene group, and (iii) an
all-E-triene group conjugated with the diacetylene. Cicutoxin is known to act
directly on the CNS, and is responsible for tonic and clonic convulsions and
respiratory paralysis [Uwai et al., 2000 (33)]. Despite cicutoxin is a severe
convulsant compound, its mechanism and structure-activity relationships (SARs)
is little known because of its chemical instability. To be able to comprehend the
features of these type of substances, it is necessary to study the principal
structural properties for the toxicity of polyacetylenes. Additionally, these studies
can very well lead to better understanding of the reaction mechanisms and give
information when developing new anticonvulsant drugs.

Larsson | Some history and effects of Conium maculatum L.

7. Biological activity
7.1. General
The piperidine toxins from the Conium (and also Lupinus and Nicotioana) species
induce cleft palate and contracture skeletal malformations in livestock, as was
mentioned above [James et al., 1992 (14)]. Different chemical structures of the
piperidine toxins from each plant lead to different toxic potencies [James et al.,
2004 (34)]. These differences are important in the mechanisms of action, such as
reduction of fetal movement and fetal malpositioning [James et al., 2004 (15)].
The induced cleft palates by toxic plants in goats look closely like the cleft palates
induced in humans [James et al., 2004 (35,36)]. The similarity between goats and
humans in this case is also useful as a model for histological comparisons of the
prenatal- and postnatal-repaired cleft palate and comparison of craniofacial
growth and development. This is a very good congenital model to study the
etiology of cleft palate in humans and develop fetal surgical techniques in utero.
The most of the discovered biomedical applications from these plants today
derives from their relationship with similar conditions in humans [James et al.,
2004 (15,35-38). Conium alkaloids may also cross the placenta and produce a
similar sedative and anesthetic effect on the fetus as on the dam [Bunch et al.,
1992].
7.2. Symptoms of poisoning of Conium
When this group of piperidine alkaloid-containing plants is involved the
symptoms of poisoning are similar in all livestock production. The initial
symptoms includes nervousness, depression, grinding of the teeth, frothing
around the mouth, relaxation of the nictitating membrane of the eye, frequent
urination and defecation and lethargy. Then eventually follows muscular
weakness, tremors and fasciculations, ataxia, collapse, respiratory failure and
death [James, 2004]. Signs of toxicosis may appear as early as 1 h after ingestion
and get worse the next 24-48 h even if further ingestion does not occur. However,
if the animal does not die within this time frame it generally recovers completely.
Coniine and -coniceine from Conium and anabasine from N. tabacum used
identical birth defects in cattle, pigs, sheep, and goats [James et al., 2004 (15,3944)].
7.3. Pharmacological actions
Hemlock alkaloids have been found to have an action on spinal cord reflexes and
depress autonomic activity and in large quantities cause neuromuscular blockade.
This action may lead to respiratory depression and anoxic brain injury, with
eventual death following within 24 hr of ingestion. Despite rhabdomyolysis and
assosiated acute renal failure have been recorded regarding hemlock poisoning,
no direct toxic effects have been described concerning the liver or kidneys.

Larsson | Some history and effects of Conium maculatum L.

The action of poison hemlock of the central nervous system seems to play a minor
role, as the senses seemingly remains intact in humans and in animals.
Since stimulation of the sensory cells does not result in muscle contraction, there
is an increased resistance in the sensory cells [de Boer, 1950 (45)]. The influence
the hemlock alkaloids have on the heart is of minor importance. After preliminary
stimulation the sympathetic and parasympathetic ganglia become paralysed, the
same reaction takes place with the respiratory medullary center, which result in an
respiratory arrest and asphyctic agonal convulsions. de Boer has studied the
peripheral vasoconstriction effect of hemlock, and recorded varying results in
frogs and a pressor effect in mammals. When coniine and opium were combined,
the summarised result was that opium caused an emphasized effect of the
paralysing action of coniine, when coniine decreased the anesthetic effect of
opium. The character of the paralysis was more like the ascending type [de Boer,
1950].
Since the piperidines behaves in a specific way and are teratogenic they also
fulfill specific criteria for teratogenesis [James et al., 2004 (39)]. The structural
characteristics of these piperidines need to be determined and their main
differences outlined to be able to find out their mechanism of action, as fetal
movement and malpositioning. The birth defects caused by Conium, Lupinus and
Nicotiana spp., are the same and their biological activities occur by a similar
mechanism of action [James et al., 2004 (15)]. As usual with biological active
compounds one use to characterise the toxicity into acute and chronic forms.
Sollman postulated that the peripheral actions of coniine are similar to those of
nicotine, but it produces more prounounced paralysis of the central nervous
system and of the skeletal muscle nerve endings [de Boer, 1950 (46)]. de Boer
confirmed 1950 that coniine had similar activity as strychnine [de Boer, 1950].
One of the reasons why C. maculatum could not be used as a medicine was that
different preparations varied too much in their potency. Fairbairn and Challen
have found one possible explanation to the differing potency; alkaloidal content
and composition from extracts differed widely dependent on the climatic
conditions and even which time of the day the plants were collected [Bowman
and Sanghvi, 1962 (27)]. Therefore the study of the individual alkaloids
intensified. The four main alkaloids are coniine, -coniceine, N-methylconiine
and conhydrine. Conhydrine occurs in the smallest proportions and has the
weakest pharmacological action [Bowman and Sanghvi, 1962 (47)].
The most distinctive action of the three other hemlock alkaloids plus nicotine is
their ability, provided the dose is small, to inhibit the crossed extensor reflex and
the so called knee-jerk by an action potential in the spinal cord. The influence of
nicotine on the knee-jerk was first demonstrated by Schweitzer and Wright 1938
[Bowman and Sanghvi, 1962 (75)]. Since these effects also occured with small
doses, de Boers conclusion that the action of coniine was similar to that of
strychnine could not be confirmed. In fact, it was to the contrary: the actions of
the hemlock alkaloids and of strychnine were shown to be mutually antagonistic.
Since neurons in the spinal cord may both be inhibited and activated by the action
of hemlock, the mechanisms involved are a bit complicated. Both mephenesin and
strychnine are able to antagonise the depressant action of the alkaloids on the
patellar reflex. If the alkaloids initially stimulate inhibitory neurons rather than
blocking excitatory ones, the antagonistic relationship of the two substances may

Larsson | Some history and effects of Conium maculatum L.

be explained. There is evidence that its central synapse is controlled by

polysynaptic inhibitory pathways, although the patellar reflex is monosynaptic.
Mephenesin acts in the first case on spinal interneurons [Bowman and Sanghvi,
1962 (48), and by that may have an antagonistic effect of the alkaloids by
blocking the interneurons of the inhibitory pathways. Strychnine also antagonise
the actions of inhibitory transmitters in the spinal cord [Bowman and Sanghvi,
1962 (49,50)].
7.4. Acute poisoning
When exposed to non-toxic doses, a sedative or depressive effect of the central
nervous system, CNS arose, which produced deep sleep. These anesthetic effects
were observed in several piperidinic substances by Hunt and Fosbinder 1940
[Lpez et al., 1999 (56)].
Animals who survive acute poisoning from C. maculatum usually recover without
future injuries, but abortions may result [Lpez et al., 1999 (54,57)]. The
necropsy examinations are consistent with what is expected from animals
suffocated of respiratory arrest: dark and dense blood, dark congested liver, the
right side of the heart is found full of blood while the left is empty, the lungs are
congestive and dark colored, showing clear bands where the ribs have been in
contact with the lungs [Lpez et al., 1999 (53,54)]. The acute toxic activity of the
compounds coniine, -coniceine and N-methylconiine is supposed to block the
spinal reflexes through the action of the medulla: they an initial stimulus is
followed by a depression of the autonomic ganglia.
High doses of the compound produce a stimulus of the skeletal muscles and a
neuromuscular blockage through the action on nicotinic receptors. When the
phrenic nerves are affected and the respiratory muscles become paralysed death
occurs [Bowman and Sanghvi, 1963; Lpez et al., 1999 (44,55)].
7.5. Cronic poisoning
The related malformations caused by C. maculatum have been described in
calves, piglets and lambs: at birth they show arthrogryposis, scoliosis, torticollis,
cleft palate and excessive flexure of the carpal joints. These injuries were
reproduced experimentally to cows during the 55-75 days of pregnancy [Lpez et
al., 1999 (40,58-60).
If fresh hemlock was to dry under the sun during 7 days an important loss of
biological activity occurred.
7.6. Treatment
There are no known antidotes and treatment of poisoned victims consists of
supportive care including sedation, intubation and ventilation [Foster et al., 2003].
Respiratory support and gastric decontamination should be administered directly.
Anti-cunvulsants should be given when needed. Forced diuresis can be applied to
prevent renal failure from rhabdomyolysis and myoglobinuria [Frank et al.,

Larsson | Some history and effects of Conium maculatum L.

1995]. The use of stimulants and large volumes of water have been suggested as
treatments against poisoned livestock. Among human beings treatment with
alcoholic beverages, tea and coffee has been suggested and also the induction of
vomit with a tablespoon of salt dissolved in warm waters, repeating this treatment
until the vomit is empty, keeping the victim laying down, resting, covered and
under medical control [Lpez et al., 1999 (54,57)]. The reasons to why not poison
by hemlock are more frequent are the plants mousy odor, bitter taste and
burning sensation of the mouth, throat and abdomen on ingestion [Frank et al.,
1995 (61)]. A poisoned victim from hemlock stated that the plant tasted like
carrot tops [Frank et al., 1995].
Survivors of poisoning have in the most cases not shown permanent sequelae and
have neither shown any long-term damage of the liver nor kidneys. For
nonsurvivors brain death often occurs, without serious extraneural losses, thereby
making them possible multiorgan donors (read more about this at next chapter,
Hemlock victims as organ donators.

8. Hemlock victims as organ donators

Today more patients are dying while waiting for their organ transplantation,
despite the improving results of transplantations. Therefore one have investigated
the so-called mariginal donors (i.e. donors not previously thought to be usable).
Mariginal donors may be victims of poisoning, including those involving carbon
monoxide, tricyclic antidepressants, methanol, cyanide and poisonous plants.
Foster et al. have reported a case of successful transplantation of the liver, kidney
and pancreas from a 14-year old girl who accidentally had ingested fresh hemlock
on a nature hike. The cause of death was assigned anoxic encephalopathy. The
liver and kidney biopsy results showed normal values. All the three recipients had
immediate function of their organs, and no of them seemed to have any clinical
evidence of transmitted toxin. Still 6 months after transplantation, all recipients
were well, with functioning transplants. Foster et al. made the conclusion in their
report that intoxication of poison hemlock does not have to contradict organ
donation [Foster et al., 2003].

9. Structure activity relationships

The molecular structure of C. maculatum alkaloids determines its teratogenic
effect. The side chain of the molecule must be at least a propyl group to have any
effect. 2-ethylpiperidine has for instance been shown to be non-teratogenic
[Lpez et. al, 1999]. The piperidine ring must also be alpha-substituted [Bunch et
al., 1992].
According to experiments [Vetter, 2004 (60)] coniine, -coniceine and N-methylconiine were teratogenic, the other five homologous substances described in
chapter 6, The alkaloids in poisonous hemlock were not. No information has
been found considering the acute toxicity and the structure of the alkaloids
[Vetter, 2004]. If one superimposes the active alkaloids of C. maculatum and
nicotine one can see the similarities of the molecular structures and that will give

Larsson | Some history and effects of Conium maculatum L.

some clues which type of bondings there are between the alkaloids and the
nicotinic receptor. It is obvious that the nitrogen atom play a major role (since it is
apparent in all of the molecules), and the similarity between C. maculatums
alkaloids (piperidine ring and a propyl side chain in 2-position), indicates that this
is of importance.
Keeler and Balls, fed pregnant cows with structural analogues of coniine to
compare structural relationships to their teratogenic effects. The results indicated
that the piperidine alkaloids must fulfil certain chemical structural criteria to be
regarded as teratogenic. These data suggested that the piperidine alkaloids with
either a saturated ring or a single double bond in the ring with a side chain of at
least three carbon atoms in length adjacent to the nitrogen atom, were potential
teratogens [James et al., 2004 (60)]. Those alkaloids with a double bond adjacent
to the nitrogen atom are more toxic than either the fully saturated or N-methyl
derivatives [James et al., 2004 (34)].

10. History
10.1. The trial and execution of Socrates
A cocktail of extract from Conium maculatum, the poison hemlock, mixed with
opium have been reported to be the lethal poison which the Greek philosopher
Socrates was condemned to drink in the year 399 B.C. [de Boer, 1950]. Socrates
symptoms from he drank the cup to he passed away was described by Plato, who
also was a pupil to Socrates. The trial and execution of Socrates is by many
estimated to be the next most famous execution in the worlds history, next after
the crucifixion of Jesus. Jesus life, trial and execution have been documented very
well, and is world wide known, but what do we know about Socrates and his
theology and philosophy (since I bring the trial and execution of Socrates up here,
it may be interesting to know why he was sentenced to death)?

Larsson | Some history and effects of Conium maculatum L.

Figure 13. Bust of Socrates. http://www.molloy.edu/

academic/philosophy/sophia/plato/socrates.htm.

The trial of Socrates in 399 B.C. confronted an old desire for restful social life
and a new idea of human dignity, in a legal system where trial by jury was in its
infancy in a primitive, experimental stage. Socrates postulated to his defense, that
his claim on free inquiry would make him to an official benefactor and not any
criminal. He failed to convince the jury of 501 delegates and was found guilty and
sentenced to death [Brumbaugh, 1989].
Socrates was prosecuted by a younger man named Meletus. His charge against
Socrates was impiety. The more specified arguments that Socrates was supposed
to be impious were
1. Socrates did not recognise the gods of the city.
2. He invented new divine things.
3. He was charged to corrupt the youth.
There are different reports about the defence Socrates gave about the charges
against him. Some sources have said him to be silent during the trial, but
Xenophons and Platos statements are to the contrary. Xenophon was a famous
soldier at that time and a friend of Socrates and have published a report named
Memorabilia. [Brumbaugh, 1989]. Socrates speech was perceived by many to
have been quite haughty and proud. Xenophon characterise it as megalegoria,
which can be translated as big talk [Brickhouse and Smith, 2002].
Xenophon interpreted Socrates behaviour at the trial as he did not want to die in
old ages and pain and decided to end his life as a martyr. He also concluded that
Socrates had religious scruples about suicide and thereof he provoked the court
[Brumbaugh, 1989]. This Xenophon explains as Socrates big talk at his trial. In
Platos version, Socrates claims that it is his duty as a defendant to instruct and
persuade the jury. The big talk in Socrates defense is by many scholars only the

Larsson | Some history and effects of Conium maculatum L.

natural result of a mission given to him by the god of Delphi (Apollo)

[Brickhouse and Smith, 2002]

Figure 14. Xenophon.

http://www.philosophypages.com/dy/x.htm#xenp.

To be able to get a picture of why Socrates was accused for not recognise their
gods, one need to understand a little of the situation in Greece at that time and
Socrates philosophy. Since this is neither any history nor philosophy thesis, it
will only be touched very briefly here.
The Athenian expansion during the fifth century B.C. collided to some degree
with Sparta and its allies, and for thirty years hot and cold warfaring occured
alternately, which ended with the total defeat of Athens in 404 B.C. Then Sparta
supported an interim council of representatives of the conservative group of a
party named The Thirty Tyrants took over the government [de Boer, 1950]. The
more active democratic leaders fled from the city, and Critias, the leader of The
Thirty Tyrants, instituted a reign of terror. Since they were short of public
revenues, they took advantage by a law that the property of traitors could be
confiscated by the state. Wealthy foreign residents (and some others) could be
arrested and executed for treason after secret cross-examinations, and by that they
managed to keep the treasury solvent. Critisism of the reign was almost the same
as being quieted by assassination [Brumbaugh, 1989].
The most fundamental dogma of the Socratic theology is that the gods are truly
wise. Socrates reasoned, that wisdom guaranteed virtue, which followed that the
gods are completely virtuous. Socrates claims that humans get nothing good that
does not come from the gods.
This line of reasoning explains why Socrates found the ancient Greek myths who
were fighting with one another hard to believe, because disagreements would by
that logic reasoning not exist, and hence they should never fight. Moreover, the
gods would never, in Socratess view, do anything evil or harmful. This reasoning
was by many at this time seen like he questionized the ancient Greek mythology,
which seemed to be very fatal [Brickhouse and Smith, 2002].

Larsson | Some history and effects of Conium maculatum L.

10.2. The death of Socrates

The first noteworthy thing in the description of Socrates execution is that his legs
could not carry the weight of his body, so he had to lay down. At the same time
Socrates felt a cold sensation in his feet. Both the strong vasoconstriction, the
cyanosis and the curare-like action played a part to the total effect of coniine. The
sensibility of the skin is strongly impaired, or maybe paralysed, this symptom is
not a special feature of coniine poisoning. The peripheral paralysis in Socrates
case could not have proceeded far, since he was still able to talk and to move
away his blanket. It is evident from records that Conium poisoning affects
swallowing and speech, particularly at the end of the process. None of these
symptoms is described in Phaedo, where Plato describes how Socrates dies by
poisoning from hemlock, after agonal convulsions death arrived. Plato would
unlikely miss such symptoms as ataxia, convulsions, tremors and spastic rigidity,
as normally occurs in Conium poisoning [de Boer, 1950].
However, as Plato describes the scene and the effects of the hemlock on Socrates
there are certain curious features. In the Phaedo, hemlock just produces first
heaviness and then numbness in the body. The numbness starts in the feet and
then proceeds gradually upwards, to the groin and when the heart is affected, he
dies [Gill, 1973]. His mind remainied clear until the end, and his death arrived
calmly and peacefully. It is remarkable account, rich in emotive power and in
clinical detail [Brickhouse and Smith, 2002 (63)].

Figure 15. Plato. http://www.philosophypages.com/ph/plat.htm

The only other symptom he mention in Phaedo is a single movement prior to

death. The symptom of numbness in the lower legs have also been registered in
other ancient documents. Modern medical authorities recount more effects of this
kind, as salivation, nausea, vomiting, dryness and choking in the lower throat,
dilated pupils, blurred vision and hearing and thick speech. Arms and legs
becomes paralysed, which often is accompanied by spasms and convulsions. Thus

Larsson | Some history and effects of Conium maculatum L.

Platos only describe two of the symptoms of hemlock-poisoning, and his

description of the death scene in the Phaedo gives a quite different impression of
the effects compared with the medical accounts. In Platos point of view is the
hemlocks penetration into the body a calm, almost rythmic process. This is
contrast to how the second century writer Nicander describes it. There are many
theories why Plato gave such very short description of Socrates symptoms. One
theory is that Socrates covered his face with clothes or hands and then Plato could
not see his heavy salivation, eye rolling, dilated pupils etc. One another is that he
may have made his selection of symptoms: As so often, especially in ancient
times, big heroes were described almost as half-gods. Even if it was unconciously,
Plato may have wished to show Socratess physical toughness and stoicism, that
his mind totally was able to control his body. His description of Socrates death
may be the purification of the psyche from the body, which begins in the lower
part of the body and goes upwards [Gill, 1973].
The fact that Socrates was still able to speak until a few minutes before he
deseased, does not mean that his cerebral function was unaffected, because he
was laying down without speaking for some time, or moving and reacted only
when he was spoken to. This is comparable with a study made by de Boer, where
rats could be awaked very easily after administered a mix of coniine and opium.
The sudden death of Socrates which occured one or two minutes after his last
words is similar to the death of Britannicus. Platos description of Socratess
death seems to be a rather short process. As death must be sure in executions, the
dose of the poison must have been a large one. As mentioned above in this article,
an insufficient quantity of C. maculatum gives the opportunity to recover
completely. For a such quick and sudden death by Conium juice alone, the
quantity of poison had to be so overwhelming that it would be impracticable.
Based on this reasoning, de Boer estimates the death of Socrates to be the
outcome of the administration of Conium maculatum juice mixed with opium [de
Boer, 1950].
But is Platos records about Socrates death true then? When putting all the pieces
of information of old and new records we know together, many scholars still think
he did tell the truth, despite all the doubts mentioned above [Brickhouse and
Smith, 2002 (63)].

Larsson | Some history and effects of Conium maculatum L.

Figure 16. Totenmahl relief known formerly as the "Death of Socrates"

From Svoronos 1903-12, pl. 83. http://www.perseus.tufts.edu/cgibin/image?lookup=Perseus:image:1998.01.0083.

Tacitus described the execution of Britannicus, who was poisoned by a mixture of

C. maculatum and opium by the Roman emperor Nero [de Boer, 1950 (62)].
The plant have been used in ancient Anglo-Saxon medicine, and its English name
hemlock is derived from the Anglo-Saxon words hemlic or hymelic. Through
the centuries its name has taken many forms, like hymlice, hymlic, hemeluc,
hemlake, hemlocke and finally hemlock [Vetter, 2004]. It was William
Shakespeare who first used the modern spelling hemlock in his Life of Henry the
Fifth [Vetter, 2004 (64)]. Conium maculatum was used as a remedy to treat
herpes, erysipelas (a form of superficial cellulites) and breast tumours. Dried,
stored and unripe Conium seeds have also been used as an antispasmodic, a
sedative or an analgesic. The dried leaf and juice of the plant were listed in
pharmacopeias of London and Edinburgh from 1864 to 1898 and the last official
medicinal recognition appeared in the British Pharmaceutical Codex of 1934 in
Great Britain [Bowman and Sanghvi, 1963]. As mentioned above, the direct
medicinal usage of hemlock is difficult since the small limit between the
therapeutic and poisonous levels [Vetter, 2004 (65)]. Greek and Arabian
physicians have used the plant to treat indolent tumours, swellings and pains of
the joints. The bitter juice of the plant was used together with betony (Stachys
officinalis) and fennel (Foeniculum vulgare) seeds as a remedy against the bite of
a mad dog. Later in history, this plant extract have been administered as an
antidote against strychnine and other strongly poisonous compounds, when
nothing else was supposed to help [Vetter, 2004 (66)]. During the 15th and 16th
centuries religious sects used roasted roots from C. maculatum for relieving the

Larsson | Some history and effects of Conium maculatum L.

pains of gout. However, in the 1760s, it began to be used to treat cancerous ulcers.
Only USA imported about 14,000 kg of seeds and 7,000 kg of dried leaves from
the drug. The tinctures and extracts were used because of their sedative, anodyne
and antispasmodic properties (in the case of asthma, epilepsy, whooping cough,
angina, chorea and stomach pains). The drug has to be given with meticulous
care; narcotic poisoning may result from internal use which can produce
paralysis. The use of C. maculatum in the medicine have been disputed. However,
it remains as a classic homeopathic agent with various uses [Vetter, 2004 (67)]. It
is known to be a long-acting remedy, it is especially of use against elderly people,
when the vital powers of the body are declining. It has also been used in the
treatment against a serious type of malignant tumour [Vetter, 2004].
During the 1800s and early 1900s the livestock industries developed rapidly in
western United States, and then the poisonous plants were soon discovered as a
source to economic loss for it. Much because of these losses, the U.S. Department
of Agriculture initiated research on the effects the poisonous plants caused on the
livestock. So far they had mostly concentrated their research to identify the
specific poisonous plants, with only limited efforts to identify plants toxins. After
the World War II more advanced and sophisticated scientific equipment were
developed and facilitated the identification of plant toxicants and the mechanisms
of their actions [James et al., 2004 (51,68)]. At this time, members of the ranching
communities asked that research be initiated on a number of problems causing
great economic loss to producers.

11. Management and control of the plant

Conium maculatum is an opportunist weed species, and has wide adaptations
ability. Poisonous hemlock is infected by virus strains like the alfalfa mosaic virus
(AMV), celery mosaic virus (CeMV), ringspot virus and carrot thin leaf virus
[Vetter, 2004 (69)]. There are methods of viral infection or phytophagous insects
to control and remove the plant, but those need more research. Mechanical control
like hand pulling or grubbing works of course, but can be very time consuming.
Hand pulling is most effective in wet soils and small infestations. The best thing
is to pull or grub out the plant prior its flowering [Vetter, 2004 (70)]. Chemical
control of hemlock is simpler if extensive areas are covered by the plant. One can
for example use a synthetic auxin-like compound, like as 2,4-D (2,4-dichlorophenoxy-acetic acid), which spare the grasses, except a few species. Since
hemlock produce so numerous seeds, a repeated treatment the following year may
be needed to eliminate the weed. Hexazone can be used to control the poison
hemlock in alfalfa [Vetter, 2004 (71)]. To avoid or minimalize the chance to plant
toxicosis one should not let pregnant animals grazing on fields when
developmental problems may occurs. One have set 70 days as a critical gestation
time for cows and 60 for pigs [Vetter, 2004].

12. Discussion

Larsson | Some history and effects of Conium maculatum L.

Pharmacologic information about the Conium alkaloids adds further biochemical

evidence upon which a mechanism of action may be hypothesized. It has been
suggested that coniine and -coniceine possess some curare-like effects [James et
al., 2004 (72)]. However, curare does not cause the initial stimulation that
Conium alkaloids do, but induces a highly selective paralysis of motor end-plates
in skeletal muscle and also paralyzes autonomic ganglion cells. The clinical
effects of curare are very similar to the depressing effect of the Conium alkaloids,
coniine and -coniceine, but less so for N-methylconiine. Could the teratogenicity
of Conium be attributed to a mechanism similar to that of curare, or is it the side
effects which are responsible for the teratogenicity? It is a matter of hypothese
whether the teratogenic effects, which are believed to be due to reduced fetal
movement during critical stages of gestation, might be attributed to the same
mechanism of action, namely, the blockade of effector cells innervated by
preganglionic cholinergic nerves in the fetus. If this is the case, then curare should
cause arthrogrypotic-type malformations in livestock similar to those induced by
Conium, assuming there were no metabolic, pharmacokinetic, or excretionary
differences. Interestingly, curare and D-tubocurarine are reported to cause
arthrogryposis in chicks when administered in eggs and cleft palate in rats [James
et al., 2004 (73)]. Furthermore, it has been demonstrated in preliminary studies
with goats that curare infused into the embryonic vesicle during early gestation
caused severe contracture skeletal defects and cleft palate similar to that induced
by Conium, Nicotiana, and Lupinus.
According to experiments made by Bowman and Sanghvi, seems the alkaloids of
C. maculatum to have a peripheral blocking action in both parasympathetic and
sympathetic ganglia in larger doses. The blocking action predominated with Nmethylconiine, but with -coniceine the stimulant phase dominated while the
blocking action was relatively difficult to demonstrate. Coniine produced in most
experiments stimulant effects, but in others, the stimulant phase was absent and
only the blocking action could be demonstrated; the summation of its action can
be described to be somewhere between -coniceine and N-methylconiine. The
neuromuscular block which the alkaloids differ in many respects from that
produced by the mere depolarising blocking drugs, decamethonium and
suxamethonium, although the alkaloids indicate a depolarising action. Generally,
the drug affinity for the acetylcholine receptors must continually be high for
persistent depolarisation. However, it appears like that the hemlock alkaloids have
a low affinity for the receptors. The alkaloids are secondary and tertiary amines
which are well absorbed after oral or subcutaneous administration, and penetrate
the blood brain barrier, BBB, where they exert central actions. Thence, the
hemlock alkaloids can penetrate cell membranes readily and indicates that their
blocking action at the motor end-plates may thereof be a consequence of an
intracellular action causes the end-plates to be inexcitable by acetylcholine
[Bowman and Sanghvi, 1962].
The acetylcholine receptors are located only on the external surface of the motor
end-plates and reaction with these receptors would might be the initial contraction
produced by large doses of the alkaloids. The relatively slow following inhibition
may be explained by that the alkaloids need time to penetrate the cell membrane
[Bowman and Sanghvi, 1962 (74)].
Experiments with cats and hens by Bowman and Shanghvi, indicate that the
failure in neuromuscular transmission exerted by the alkaloids is only partly

Larsson | Some history and effects of Conium maculatum L.

responsible on reducing the release of acetylcholine through the nerve ending.

Through Bowman and Sanghvis experiment, N-methylconiine was quickest
among the three alkaloids in onset after close arterial injection. It was also the
least readily absorbed alkaloid after oral administration. These results plus that
when injected into the carotid artery, N-methylconiine was without effect on
respiration, suggests that its inhibiting action has also a large extra-cellular
component in it. This conclusion may be correct since at body pH, the tertiary
amine has the strongest positive charge.
The mechanism of action of the C. macualtums alkaloids on neuromuscular
transmission is complex and may involve more than one site of action. This is
common with substances of this type which combine with acetylcholine receptors,
but whose action is not limited to extra-cellular receptors (unlike the quaternary
ammonium compounds, which cannot pass the cell membranes because their ion
charge).
The central depressant action occured was much longer lasting and occured with
smaller doses than the peripheral neuromuscular blocking action, and the
alkaloids might then seve as a lead compound for the synthesis of more specific
and less toxic spinal relaxants [Bowman and Sanghvi, 1962].
The term ascending paralysis is used more to illustrate the poisoning process; it
is someway difficult to represent a physiological substrate for it. There are no
evidence that the myoneural junction of the muscle of the legs should be
paralysed more rapidly than those of the arms, thorax and head. Following that
line of reasoning, there should be one or more factors which induce this
phenomenon. One explanation to it have been proposed by de Boer:
The relationship with vasoconstriction and distance are invertedly related; the
resistence for the circulation will increase with the distance from the heart. Since
coniine indeed causes a strong vasoconstriction and depressor effect, the blood
circulation in the outmost periphery is affected very strongly, if there is any
circulation at all. The results of both of these actions is that less blood is reaching
the muscles. The muscles ability to do work diminishes strongly when they do
not recieve sufficiently oxygenated blood. Since coniine causes cyanosis by
central depression of the respiration, anoxemia occurs. Thus, the state called
ascending paralysis is a summarized effect of partially the curare-like muscle
relaxing action and partially by the vasoconstriction, lowered blood flow and
central respiratory depression, which causes anoxemia. Since this state is not any
pure paralysis it would may be better using another term than ascending
paralysis for this phenomenon [de Boer, 1950].
The reason for the variation in susceptibility among a range of species to
teratogenicity against coniine is unknown.
Different theories have been proposed, like divergencies in receptor affinity,
number or subtypes or coniine biotransformation [Forsyth et al., 1996].

13. Summary and conclusion

Some of the information given in the reports seems to be ambiguous and even in a
few cases contradictory. But one should have in mind that the reaction mechanims

Larsson | Some history and effects of Conium maculatum L.

appear to be very complicated, and the alkaloids of Conium maculatum have only
been known for a few decades.
There are four drug and medicinal related questions which raises when one
studying Conium maculatum:
1. Has coniine etc. a sufficiently potent curarizing action to justify its use in
human surgery (there are of course other interesting biological activities to
study, like the potency for skeletal deformities, but this seems too difficult to
see at this stage how it can be used in drug development)?
2. If the side effects of the crude compounds (coniine, -coniceine, etc.) are too
serious, can they serve as lead comounds for research of muscle relaxing
drugs?
3. When the reaction mechanisms are known, is it possible to develop some form
of antidote or prophylaxis against poisoning of C. maculatum?
4. Why does the susceptibility among the species vary so much in teratogenicity
against poison hemlock?
Or put it in another way: Is there any possibility to separate the unwanted side
effects from the desired effects?
One good starting point could be to study those animals which have developed
resistance against C. maculatum, and see if they have any special enzymes, or
biotransformation systems or sequestering the compounds for example. One
another could be to look at the structure-activity relationship, SAR, between the
different species bioactive compounds which are responsible for e.g. teratogenic
skeletal malformation, and see what they have in common.
As mentioned above in the text, if the victim can survive the first critical period of
poisoning, the chance to recover without any further injuries is relatively big, so
more research in this area is needed to unravel the connection between cause and
effect.

14. Acknowledgements
I want to thank my supervisor Lars Bohlin.

15. References
When the reference is enclosed in square brackets, it means that it can be found in
this list. If it is followed by a number within parantheses, it can be found in next
chapter, Further readings.
The Bantam Medical Dictionary; 3rd revised ed., The Editors of Market House
Books Ltd, Bantam Books, 2000.
Boer, J. de; Arch. Int. Pharmacodyn., 83: 473-490, 1950.
Bowman W. C. and Sanghvi I. S.; Pharmacological actions of hemlock (Conium
maculatum) alkaloids; J. Pharm. Pharmacol., 15, 1-25, 1962.

Larsson | Some history and effects of Conium maculatum L.

Brickhouse, Thomas C. and Smith, Nicholas D; The Trial and Execution of

Socrates; Oxford University Press, Oxford, New York, 2002.
Brumbaugh, Robert S.; Platonic Studies of Greek Philosophy; State University of
New York Press, Albany, 1989.
Bunch T.D., Panter K.E. and James L.F.; Ultrasound Studies of the Effects of
Certain Poisonous Plants on Uterine Function and Fetal Development in
Livestock, J. Anim. Sci., 70: 1639-1643, 1992.
Corsi, Gabriella and Biasci, David; Secretory Structures and Localization of
Alkaloids in Conium maculatum L. (Apiaceae); Annals of Botany 81: 157-162,
1998.
Dodds, Catherine J.; Henderson, Ian F.; Watson, Peter and Leake, Lucy D.;
Action of extracts of Apiaceae on feeding behavior and neurophysiology of
the field slug Deroceras reticulatum; Journal of Chemical Ecology, Vol 25,
No. 9, 1999.
Dorlands Illustrated Medical Dictionary, W.B. Saunders and Company,
Philadelphia, 2000.
Fortsyth, Carol S.; Speth, Robert C.; Wecker, Lynn; Galey, Francis D. and Frank,
Anthony A.; Comparison of nicotinic receptor binding and biotransformation
of coniine in the rat and chick; Toxicology Letters 89: 175-183, 1996.
Foster, Preston F.; McFadden, Raul Trevino; Galliardt, Scott; Kopczewski, Lea
Ann; Gugliuzza, Kristene; Gonzalez, Zulma and Wright, Francis; Successful
Transplantation of Donor Organs From a Hemlock Poisoning Victim, Vol 76,
No. 5, p. 874, Received 24 January 2003, Revision Requested 21 February.
Accepted 10 april 2003.
Frank B.S, Michelson W.B., Panter K.E., Gardner D.R.; Ingestion of Poison
Hemlock (Conium maculatum); West J. Med., 163:573-574, 1995.
Gill, Christopher; The Death of Soocrates, Classical Qarterly NS 23; 25-58,
1973.
International Dictionary of Medicine and Biology, Vol 1 and 3, John Wiley &
Sons Inc., 1986.
James, Lynn F.; Panter, Kip E.; Gaffield, William and Molyneux Russell J. ;
Biomedical Applications of Poisonous Plant Research; Poisonous Plant
Research Laboratory, Agricultural Research Service, U.S. Department of
Agriculture, 1150 East 1400 North, Logan, Utah 84341, and Western
Regional Research Center, Agricultural Research Service, U.S. Department of
Agriculture, 800 Buchanan Street, Albany, California 94710 Received for
review December 16, 2003. Revised manuscript received March 5, 2004.
Accepted March 5, 2004.
Lpez A., Cid S., and Bianchini L.; Biochemistry of hemlock (Conium
maculatum L.) alkaloids and their acute and chronic toxicity in livestock. A
review. Toxicon, 37: 841865, 1999.
Vetter; J.; Poison hemlock (Conium maculatum L.); Faculty of Veterinary
Science, Department of Botany, Szent Istvn University, 1400 Budapest, Pf.
2., Hungary. Received 18 January 2004; accepted 16 April 2004. Available
online 15 June 2004.
The chemical structures have been drawn by ISIS Draw 2.3.

Larsson | Some history and effects of Conium maculatum L.

16. Further readings

For the interested reader who want to know more about this plant here are a
number of articles related to it.
1. Holm L., Doll J., Holm E., Pancho J. and Herberger L.; Conium
maculatum.In: World Weeds. Natural History and Distribution; J. Wiley and
Sons, New York, pp. 221225, 1997.
2. Kielland J. and Anders O.; Conium maculatum in Hedmark county, Eastern
Norway. Blyttia 56: 9293, 1998.
3. Panter K.E. and Keeler R.F.; The hemlocks: poison-hemlock (Conium
maculatum) and water hemlock (Cicuta spp). In: James, L., Ralphs, M.,
Nielsen, D. (Eds.), The Ecology and Economic Impact of Poisonous Plants on
Livestock Production. Westview Press, London, pp. 207235, 1988.
4. Cabrera A.; Conium maculatum. In: Flora de la Provincia de Buenos Aires,
Part IV.; Coleccin Cientfica del INTA, Buenos Aires, pp. 389390, 1965.
5. Ragonese A. and Milano V.; Vegetales y Sustancias Txicas de la Flora
Argentina, 2nd ed. Editorial ACME, Buenos Aires, pp. 229231, 1984.
6. Marzocca A., Mrsico O. and Del Puerto O.; Conium maculatum. In: Manual
de Malezas, 4th ed. Editorial Hemisferio Sur, Buenos Aires, pp. 357359,
1993.
7. Panter, K.E., James, L.F., Keeler, R.F., Bunch, T.D.,. Radioultrasound of
poisonous plants-induced fetotoxicity in livestock. In: James, L.F., Keeler,
R.F., Bailey, E., Jr., Cheeke, P., Hegarty, M. (Eds.), Poisonous Plants.
Proceedings of the Third International Symposium. Iowa University Press,
Iowa, pp. 481488, 1992a.
8. Panter, K.E., Keeler, R.F., James, L.F. and Bunch, T.; Impact of plant toxins
on fetal and neonatal development: a review. J. Range Manage. 45:5257,
1992b.
9. Mitich W.; Poison-hemlock (Conium maculatum L.); Weed Technology; 12:
194197, 1998.
10. Baskin C. and Baskin J.; Germination ecophysiology of herbaceous plant
species in a temperate region; Am. J. Bot. 75, pp. 286305, 1998.
11. Clapham A.R., Tutin T.G. and Warbung E.F.; Flora of the British Isles.
Cambridge University Press, Cambridge, 1962.
12 Garraway R.; The action of semiochemicals of olfactory nerve activity and
behavior of Deroceras reticulatum (Mll.), J. Mollusc. Stud. 45: 167-171,
1992.
13. Keeler R.F. and Crowe M.W.; Anabasine, a teratogen from the Nicotiana
genus. In: A.A. Seawright, M.P. Hegarthy, L.F. James and R.F. Keeler (Ed.)
Plant Toxicology p. 324, 1985. Queensland Poisonous Plants Committee,
Queensland, Australia.
14. Panter K.E., Keeler R.F., Bunch T.D. and Callan R.J.; Congenital skeletal
malformations and cleft palate induced in goats by ingestion of Lupinus,
Coium and Nicotiana species. Toxicon 28:1377, 1990a.
15. Panter K.E., Keeler R.F., Bunch T.D. Sisson D.V. and Callan R.J.; Multiple
congenital contractures (MCC) and cleft palate induced in goats by ingestion
of piperidine alkaloid-containing plants. Reduction in fetal movement as the
probable cause. Clin. Toxicol. 28:69, 1990b.
16. Penny R.H.; Hemlock poisoning in cattle. Vet. Rec. 65: 669670, 1953.

Larsson | Some history and effects of Conium maculatum L.

17. Panter K.E., Keeler R.F., Buck W. and Shupe J.L.; Toxicity and teratogenicity
of in swine. Toxicon 20 (Suppl. 3): 333336, 1983.
18. Capithorne B.; Suspected poisoning of goats by hemlock (Conium
maculatum); Vet. Rec. 49: 10181019, 1937.
19. Jessup D., Boermans H. and Kock N; Toxicosis in tule elk caused by ingestion
of poison hemlock. J. Am. Vet. Med. Assoc. 9: 11731175, 1986.
20. Frank A. and Reed W.; Comparative toxicity of coniine, an alkaloid of
Conium maculatum (poison hemlock), in chickens, quails, and turkeys; Avian
Dis. 34: 433437, 1990.
21. Berenbaum R. and Harrison L.; Agonopterix alstroemeriana (Oecophoridae)
and other lepidopteran associates of poison hemlock (Conium maculatum) in
east central Illinois; Great Lakes Entomologist 27:1-5, 1994.
22. Nitao, J.K.; Tests for toxicity of coniine to a polyphagous herbivore, Heliothis
zea (Lepidoptera: Noctuidae). Environmental Entomology 16: 656663, 1987.
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Academic Press, 267-277, 1971.
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The biology and chemistry of the Umbelliferae. London: Academic Press, 325336, 1971.
26. Cromwell B.T.; the separation, micro-estimation and distribution of the
alkaloids of hemlock (Conium maculatum L.). Biochemical Journal 64: 259266, 1956.
27. Fairbairn J.W. and Challen S.B.; The alkaloids of hemlock (Conium
maculatum L.). Distribution in relation to the development of the fruit.
Biochemical Journal, 72: 556-561, 1959.
28. Panter K.E., Keeler R.F. and Baker D.; Toxicoses in livestock from the
hemlocks (Conium and Cicuta spp.). J. Anim. Sci. 66, pp. 24072413, 1988b.
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30. Leete E. and Adityachaudhury N.; Ibid., 6, 219, 1967.
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1975.
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Nicotiana species. In Toxic Plants and Other Natural Toxicants; Garland, T.,
Barr, A. C., Eds.; CAB International: New York, pp 345-350, 1998.
35. Weinzweig J., Panter K. E., Pantaloni M., Spangenberger A., Harper J. S.,
Edstrom L.E., Gardner D. R. and Wierenga T.; The fetal cleft palate: I.
Characterization of a congenital model. Plastic Reconstr. Surg., 103: 419-428,
1999a.
36. Weinzweig J., Panter K. E., Pantaloni M., Spangenberger A., Harper J. S., Lui
F., James L.F. and Edstrom L. E.; The fetal cleft palate: II. Scarless healing
after in utero repair of a congenital model. Plastic Reconstr. Surg., 104: 13561364, 1999b.
37. Panter, K. E. and Keeler, R. F.; Induction of cleft palate in goats by Nicotiana

Larsson | Some history and effects of Conium maculatum L.

glauca during a narrow gestational period and the relation to reduction in fetal
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41. Keeler, R. F. and Crowe, M. W. Teratogenicity and toxictiy of wild tree
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43. Panter K. E., Keeler R. F. and Buck W. B.; Induction of cleft palate in
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44. Panter K. E., Bunch T. D., Keeler R. F. and Sisson D. V.; Radio ultrasound
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Group, p. 85, Ann Arbor. Michigan: Edwards Brothers Inc., 1936.
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52. Hulbert L. and Oehme F.W.; Conium maculatum (poison hemlock) In: Plants
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