STRYCHNINE

Marc Duque
Pol Torrent
Mateu Montserrat
Jorge Lzaro

Grau de Bioqumica
Universitat de Barcelona

Index:

Introduction ...................................................................................................................... 3
Strychnine structure, origin, synthesis, history and medical uses .................................... 3
Analysis of strychnine misunderstandings in literature and popular culture.................... 5
The Joker and his permanent grin. Mode of action of strychnine. ............................... 5
The incredible Colonel Aureliano Buenda. Strychnine symptoms and treatment. ... 11
Strychnine as a cardiac tonic and sleep powder ......................................................... 14
Conclusion ...................................................................................................................... 18
Bibliography ................................................................................................................... 19

Introduction
Poison is definitely among fictions greatest weapons. Strychnine, because of its
lethality and its painful way to kill, has captivated some of the most recognised authors
worldwide. Sir Arthur Conan Doyle, Agatha Christie, H. G. Wells or Gabriel Garca
Mrquez have used it in some of their stories. Onscreen, strychnine has appeared on
films such as Psycho (1960) or The Grand Budapest Hotel (2014).
The scope of this work is to analyse how strychnine has been used in literature and film;
focusing ourselves on some specific cases, we are going to discuss about how possible
they really are from a scientific point of view and whether the explanations given by the
author in each case are correct. Obviously, we will need to explain what exactly
strychnine is, where it comes from, and its effect on living organisms.

Strychnine structure, origin, synthesis, history and medical

uses
Strychnine (C21H22N2O2) (Figure 1) is a
terpene indole alkaloid, meaning it is a
nitrogen containing natural compound that
includes on its structure an indoline (indole
with the 2-3 bond saturated) and isoprene
groups. The molecule has an intricate
structure involving seven rings, a tertiary
amine, an amide, an ether and an alkene. The
naturally occurring compound is also chiral
with a total of six asymmetric carbons.
Strychnine is one of the most complex natural
products of its size.

Figure 1. Chemical structure of strychnine

This highly toxic molecule is produced by some plants from the strychnos genus. Its
main source is the nux vomica tree (Strychnos nux-vomica), native to India and
Southeast Asia. Strychnine is majorly found on the seeds of the tree (Figure 2), together
with brucine and other alkaloids such as vomicine and igasurine. The seeds contain 2.63% total alkaloids, out of which 1.25-1.5% is strychnine and approximately 1.7%
brucine. The natural role for strychnine and the other
alkaloids is defence against herbivore.
The biosynthesis of strychnine (Figure 3) starts with the
condensation of tryptamine with secologanin following
a Pictet-Spengler type reaction catalysed by
strictosidine synthase [2] to obtain strictosidine.
Figure 2. Strychnos nux-vomica
seeds, the main source of
strychnine [1]

Strictosidine then reacts to form geissoschizine. When geissoschizine forms

dehydropreakuammicine the characteristic framework of Strychnos alkaloids appears [3].
The hydrolysis of the methyl ester and decarboxylation leads to norfluorocurarine. The
next step is the obtaining of the Wieland-Gumlich aldehyde. In its open form, WielandGumlich aldehyde can react to form prestrychnine to finally obtain strychnine. The
metabolic pathway that leads to the strychnine biosynthesis has been elucidated by the
isolation of the intermediates from the strychnos nux-vomica, only the enzyme that
catalyses the first reaction has been identified.

Figure 3. Strychnine biosynthesis pathway [3]

The toxic and medicinal effects of Strychnos nux-vomica have been well known from
the ancient times in India, although strychnine itself was not identified until 19th
century. The plant arrived to Europe near the 15th century as a rodenticide; there are
records of strychnine used to kill animals as back as 1640. It was first isolated on 1818
by Pelletier and Caventou and its elemental composition established 20 years later by
Regnault. The elucidation of strychnine constitutional structure and synthesis
represented one of the major achievements of classical organic chemistry. Degradative
work started in the 1880s and lasted until 1946 when Robin Robertson finally
determined it. The total synthesis of the molecule was achieved for the first time by
Robert B. Woodward in 1954. Both Robertson and Woodward became Nobel
Laureates in 1947 and 1965 respectively for their studies and synthesis.
As said before, the nux-vomica effects have been known since the times of ancient India
and its properties has been used for many ailments in the traditional Oriental medicine.
We can perfectly assume that the properties of the Strychnos nux-vomica are those of
the strychnine. The main historical application for the seeds have been the treatment of
dyspepsia, it is said that the bitter taste of strychnine increases appetite and the flow of
gastric juice, in addition to peristalsis stimulation [4]. These effects have not been
scientifically proven, but being this the main application for strychnine in medicine it
probably might be true. Another typical use for strychnine has been the preparation of
stimulant tonics, this part will be analysed in depth later. Modern studies have also
proven the effectiveness of strychnine in illnesses such as gastric carcinoma [5], diabetes
[6][7]
and allergy treatment [8]. However, the elevated toxicity of strychnine makes its
usage unviable as a recognised drug.
4

Analysis of strychnine misunderstandings in literature and

popular culture
The Joker and his permanent grin. Mode of action of strychnine.
Introduction
As we have already seen, strychnine is an alkaloid whose natural source, seeds from
Nux Vomica, is mainly located in Africa, Asia and South-America. This fact has not
stopped its use all around the world and through the centuries, and since it first arrived
from Asia to Europe in the XVII century as a rodent killer, has become a well-known
poison in Western literature and culture.
The first case we will see as a misunderstanding or inaccurate
treatment of strychnines biochemical properties, takes us to
the dark city of Gotham. Gotham by Gaslight is a DC-comics
series published in February 1989 as a one-shot, being the first
comic where the same heroes and villains from previous
releases were involved in different stories (no continuity). In
Gotham by Gaslight, Bruce Wayne returns to Gotham City, by
Dr. Freud recommendation, where he takes the mantle of
Batman to fight criminals, such as Jack the Ripper.

Figure 4. The permanent

grin as it appears on
Gotham by Gaslight

Although this is the main plot, we focused on a criminal, who

is suspected to have killed ten of his wives, by strychnine poisoning, and finally
attempted to kill himself. This criminal, is hypothesized to be the Joker, the main villain
for Batman in DC Universe, making a cameo appearance, which may present a new
origin for his macabre smile.
As the comic says:Tried to kill himself when we caught him. The loon took some of his
own poison. Not enough. Didnt kill himjust paralyzed his face. Happy looking
Jasper,eh? (He shows an image of a man with a forced smile, Figure 4) [9].
Hence, we will analyze strychnines mechanism of action and pathology in humans, to
see whether or not our alkaloid could be behind this famous smile and point which are
the weak points.
The GlyR receptor and strychnine: Selective antagonism
Glycine (2-aminoetanoic acid) is an amino acid which also serves as a neurotransmitter
mainly with inhibitory consequences in the brainstem and the spinal cord (GABA
neurotransmitter in the other regions). Nevertheless, it has been shown, that glycine acts
as an agonist along with glutamate in the prosencephalon, by activating the N-methylD-aspartate receptor [11].
5

Thus, adding the latter excitatory action plus the inhibitory on the GlyR receptor,
glycine may cause a wide range of neuronal and motor activities. We may only focus in
the inhibitory activity of the neurotransmitter, as it is of interest for strychnine
interaction.
As we may know, neurotransmitters are a family of biomolecules, showing some
homologies (such as amino-acidic origin, but that bind to specific receptors after
secretion from the synaptic endosomes into the synaptic cleft. From now on, we will
refer to substances which bind neuronal receptors and activate them as agonist, and to
those which bind the receptor without any direct biological response, as antagonists.
Antagonists can be either competitive or non-competitive, if they share or not the
binding site with the natural agonist.
It is also important to introduce the membrane
rest potential, which is the electric potential
loosely defined as
(Figure 5,
A). Electrical impulse (action potential) is
transmitted as depolarization
created
+ +
2+
by positive ions entrance (Na /K /Ca ) to the
cytoplasm (B). This stimulus might cause
depolarization
in
other
regions
or
neurotransmitters secretion, when V rises above
a concrete threshold. Another interesting state is
hyperpolarization, where
, created
+
when excess K ions leave the cytoplasm or
negative ions (Cl-) enter the neuron. Here,
inhibition may be accomplished by making
neurons insensitive: depolarization from other
zones is muted due to the lower membrane
potential; the action potential threshold
rises(C).[14]

A
C

Figure 5. This imatge shows diferent

stages of nerve impulse transmission.
Inhibition is accomplished through C.

Glycine is synthesized from serine, and serine is in turn generated from 3phosphoglycerate [10]. They are, consequently, not essential amino acids, though glycine
is often referred as conditionally essential, in especial states such as severe
malnourishment. Our neurotransmitter binds the extracellular unit of the receptor GlyR,
which consists of a 48KDa subunit, called the subunit, and a 58KDa subunit,
subunit. This receptor might actually be a mutation from a single chloride ancestor
gene [20], as this is the function the transmembrane domain exerts: when glycine binds to
the -subunit, plasmatic membrane conductance of Cl- is increased (because they can
enter the cell through the gated channel).

As we have seen, this generates a hyperpolarization state which silences other

depolarizing stimuli (created e.g for glutamate or acetylcholine in motor neurons). We
might point out, this hyperpolarization is also controlled: if the membrane potential
lowers to -70mV, the difference between high extracellular and low cytoplasmic
chloride ions concentration, creates an electrochemical gradient, translated in a
depolarization. This illustrates the complex nature of nerve impulse transmissions, and
serves to remark the simplification we have make to understand strychnines action.
Here is where strychnine plays a part in inhibition of inhibition. According to our
classifications, strychnine is a selective (because it just attacks glycine receptors)
competitive antagonist of the GlyR receptor. Both glycine and strychnine bind to the
48KDa subunit, but not at the same residues (really close). Previous studies [17][19],
assigned strychnine binding sides to residues 197-202, where it interacts with tyrosine
through aromatic energy transfer [20], and glycine to the 190-196.
If glycine cannot activate the chloride receptor channels, uncontrolled glutamatergic
depolarization occurs which in turn activate motor neurons, leading to muscular
overexcitation, this time through acetylcholine release (Figure 6). However, this doesnt
mean the membrane potential is always lower than the rest state in a strychnine
poisoning: ion pumps transport K+ ions outside the cell to return to the rest potential, but
it is not exceeded. Hyperpolarization is never achieved and so modulation disappears,
leading to uncontrolled excitation: even a tiny pulse from a far neuron can rise the
potential above the threshold. It is important to remark the loss of modulation; a neuron
in a normal state, receives many impulses, and for a correct nervous function, it might
only generate an action potential in some cases. During strychnine action, as we have
said, any impulse generated by sensory neurons will create a chain reaction, visible as
muscle spasticity.
This is in agreement with strychnines poisoning pathology, which we will comment in
detail in other sections, which includes muscle contraction and tetany, and may lead to
death. It doesnt still explains how a specific and localized muscle contraction, such as
the permanent smile contraction, may be accomplished.

A.

B.

Excitatory impulse

t(ms)
Hyperpolarization

Strychnine action

Figure 6 A) Scheme made with Chem-Bio Draw which summarize the antagonist action of strychnine. The
alkaloid binds to the 48KDa subunit and inhibits hyperpolarization, by competing with glycine. N impulses
provoke an action potential on the corticospinal neuron and depolarization is not muted; calcium voltagegated channels are activated and glutamate vesicles are secreted to the synaptic cleft. The signal is transmitted
through the motor neuron and acetylcholinergic excitation of muscles by the nicotinic acetylcholine receptor
leads to spasms and tetany.
B) The first two graphics show normal glycine inhibition through hyperpolarization of the corticospinal
neuron: excitatory depolarization and a low membrane potential induced by chloride ions, sum up. The result
(second graphic), doesnt surpass the threshold and so the rest potential (-65 mV) is almost instantly
achieved. In absence of inhibitory modulation, the membrane potential rises above the threshold and
generates an action potential (spike), that will be transmitted to the motor neuron.
8

Myostatic contraction and localized strychnine poisoning

As we have seen, typical strychnine poisoning is not a viable cause for the Jokers grin:
given intravenously or orally (as the comic suggests) it would rapidly extent through the
nervous system, causing contraction and spasms on almost every group of muscles in
his body, and hence not only focusing on the smiling muscle.

Figure 7. Scheme which shows the zygomaticus

major muscle and its connexion with the orbicularis
oris. In red, the bucal and zygomatic branches of the
facial nerve.

By smiling muscle, we refer to the zygomaticus major muscle. This muscle extends
from each cheekbone to the corners of the mouth, where it connects with orbicularis
oris muscle (this muscle closes the mouth and puckers the lips when it contracts). The
zygomaticus muscle is activated by the brainstem through the VII cranial nerve, known
as facial nerve and its extracranial branches. Apart from directing facial expression, this
nerve is also implied in taste sensation and submandibular gland excitation by the
parasympathetic system [12]. There a many muscles implied in laughing and smiling, but
we focused on the zygomaticus muscle as it is often referred to cause natural smile
(similar to the grimace a patient makes when he is asked to close his eyes tightly).
On the other hand, local tetanus causing permanent contracture is the subject of some
studies. Tetanus, is an infection characterized by spasms and tetany, so severe that even
bone fracture may occur. It is caused by the anaerobic bacteria Clostriduium tetani,
which excretes among other substances, tetanospasmin or TeTN. TeTN is a potent
neurotoxin with clinical manifestations similar to those in strychnine poisoning, but
with a different mode of action: this 150KDa protein, enters into inhibitory neurons and
interferes with exocytosis vesicles pathways that carry glycine or GABA.[13] If, for
example, glycine is not secreted into the synaptic cleft, we may be in the strychninepoisoning-like state, where hyperpolarization cannot be reached and overexcitation
leads to spasms and tetany (here used to point the involuntary contraction of muscles, a
clinical manifestation shared by both pathologies). We consider this homology enough
to relate the medical condition observed under local tetanospasmin injection with a
hypothetic strychnine injection to the zygomaticus muscle.

In [15], S.W Ranson

and C.F.Sans, differentiate between contractures(muscle
shortening) caused by continuous excitation through motor neurons, hypertonic
contractures, which disappear during sleep or under the effects of narcotics, and
myostatics contractures, where the muscle has even changed its insertion point and
may never return to the relaxed position. According to Ranson, after an appropriate
dose of tetanus toxins infection into one limb of a highly resistant animal like the cat or
the rat, tetany is fully developed in the neighboring region, with the muscle held in
continuous hypertonic contraction for days. After 5 or 7 days, permanent shortening and
so myostatic contracture is accomplished.
Conclusion for Case 1
After, analyzing strychnine mode of action, or what we know now about it, we can
conclude that an oral strychnine poisoning is not capable of generating a permanent
smile. Mainly because,
1. If the Joker survived, the dose couldnt be more than 1-2mg/kg; hence, high
concentrations of strychnine in a concrete region, such as the zygomaticus
muscle, are highly improbable.
2. We can hypothesize local strychnine-poisoning through intramuscular injection:
it could first lead to a hypertonic contraction, similar to the initial states of
induced localized tetanus. Finally, as some papers asses (see paragraph above),
we would arrive to a myostatic permanent contraction where muscles would
adapt to this new rigid position. Let the initial point of administration be the
zygomaticus major muscle, and we present the only feasible mechanism by
which the Joker would have been able to create his representative sign.
3. Even locally administrated, there are no experimental records of homology
between bacterial induced tetany and strychnine tetany, so myostatic
contractions, which are yet not fully understood, could, by some manner be
impossible through the alkaloid mechanism. As a consequence, any contracture
would be passing or end with dead, sleep or unconsciousness. Moreover,
strychnine would extent to the facial nerve from the zygomatic branch and this
would cause contraction in other muscles, improper endocrine regulation,
interference in sensitive impulses

10

The incredible Colonel Aureliano Buenda. Strychnine symptoms and

treatment.
Introduction:
The second case we will see, take us to the Colombia of the XIX century. One hundred
years of solitude is a novel by Colombian writer Gabriel Garca Mrquez that was
awarded with the literature Nobel Prize in 1982 and its considered a Spanish America
and universal literature master piece. The novel describes the multi-generational story of
the Buenda family in the fictional village of Macondo.
Despite its brilliant plot, we will focus on the Colonel Aureliano Buenda character. He
was the second son of the family and the first person that lived in Macondo. As the
character is introduced in the story, the author says: COLONEL AURELIANO
BUENDA organized thirty-two armed uprisings and he lost them all. He had seventeen
male children by seventeen different women and they were exterminated one after the
other on a single night before the oldest one had reached the age of thirty-five. He
survived fourteen attempts on his life, seventy-three ambushes, and a firing squad. He
lived through a dose of strychnine in his coffee that was enough to kill a horse. [22]
Of course, this is an exaggeration in concordance with the magical realism genre that
the author wants to achieve including magical elements in the quotidian world.
Nevertheless, we will analyze if the Colonel could have survived or not to its poisoning.

Strychnine poisoning:
As we have seen, strychnine inhibits the action of glycine leading the neuron to
uncontrolled excitation due to the inability of the membrane to hyperpolarizate. This
leads to the characteristic symptoms of strychnine poisoning.
Once ingested, like the Colonel did,
the strychnine is rapidly adsorbed by
the gastrointestinal tract as the first
symptoms appear within the first ten
to twenty minutes after exposure.
The alteration of the muscular
neurons causes the muscles begin to
spasm. Convulsions, characterised
by risus sardonicus, opisthotonus,
flexor spasm of upper limbs, and
extensor spasm of lower limbs,
occurr with minimal sensory stimuli.
(Figure 8 ) [23]

Figure 8. Illustration of strychnine convulsions

11

These convulsions are very painful because of the strong contractions of muscles, they
lead to lactic acidosis, hyperthermia and rhabdomyolysis (muscular cell breakdown) due
to muscular cells stress.
The convulsions, increase in intensity and frequency until the backbone arches
continually. If not treated, death comes within 1 to 3 hours from asphyxiation caused by
paralysis of the neural pathways that control breathing, or by exhaustion from the
convulsions. [24]
Other clinical effects might be: tachycardia, vomit, pupil dilatation and hyperreflexia.

Analysis of the Colonel Aureliano Buenda case. Strychnine LD50 and treatment:
The first thing to analyze is the median lethal dose (LD50) of horses and humans. LD50
is the dose required to kill half the members of a tested population after specified test
durations. In horses, orally taken strychnine LD50 is 0.5 mg/Kg [25] and 1-2 mg/Kg in
humas [24]. As the average horse weights 500 Kg and the average male 80 Kg, it will
take 250 mg of strychnine to kill a horse and about 100 mg to kill a man.
From this data we might conclude that the colonel must have died after its intake of
strychnine. However, we know from the novel that Colonel Aureliano Buenda was an
incredible and strong man so we will discuss if there is a reason why the Colonel could
have survived as the book says.
In order to survive, there isnt a specific antidote for strychnine but a medical treatment
can be applied. This treatment consists in trying to alleviate the symptoms and facilitate
the removal of the drug until its naturally metabolized or excreted.
Once the strychnine poisoning its confirmed, if symptoms are not showed, the first
thing to do is remove as much as the poison as its possible to prevent its absorption. It
can be done with activated charcoal or potassium permanganate solutions but it has to
be done quickly because of strychnine rapid absorption.
When the patient starts to show the symptoms it has to be taken to a quiet and dark
room since stimuli can produce convulsions. Then, the treatment is directed towards
control of convulsions and preventing of asphyxia by combination of anticonvulsants
like diazepam along with muscular relaxants and artificial ventilation [23]. If the patient
gets stable and remains free of convulsions during 6-10 hours it has a lot of chances to
survive as strychnine is rapidly metabolized and excreted from the body [26]. Total
excretion and normality is achieved in 48 hours. [23]

12

Figure 9. Tannic acid structure

However, this is the actual treatment but in the late

XIX and early XX centuries the treatment was to
administer tannic
acid
(Figure
9) which
precipitates the strychnine as an insoluble tannate
salt, and then to anaesthetize the patient
with chloroform until the effects of the strychnine
had worn off. Despite having the same basis as the
modern treatment, is not as secure and effective.
Knowing this and taking into account the
localization and the time in which the Colonel
lived we can consider that if he received some
treatment, it might not be really effective.

Another thing to bear in mind is the physical condition of the Colonel but even if he was
really robust, muscular and weighed about 180 Kg, the lethal dose of a horse would
have also killed him
A further analysis can be made taking into account the way the Colonel ingested the
strychnine. As the book says, the dose of strychnine was in its coffee and maybe other
alkaloids present there, such as caffeine, could have a positive effect alleviating
strychnine effects.
Caffeine (Figure 10) is also an alkaloid that acts as an
antagonist of brain cells adenosine receptors. With a
continued wakeful state, adenosine accumulates over time
in
the
neuronal synapse,
binding
to
and
activating adenosine receptors found on certain brain
neurons; when activated, these receptors produce a cellular
response that ultimately increases drowsiness. When
caffeine is consumed, it antagonizes adenosine receptors.
As a result, caffeine temporarily prevents or relieves
drowsiness, and thus maintains or restores alertness [27].

Figure 10. Caffeine formula

This increases the strychnine effect because the body is more sensible to stimuli and
remains in a awaken state. Also, recent studies [28] reveal that due to its structure,
caffeine could also attach to the glycine receptors like strychnine but obviously creating
a weaker interaction. Therefore, the fact that strychnine was in a coffee would decrease
the survival chances of the Colonel.
Finally, in order to survive strychnine poisoning, maybe the glycine receptors are
modified through a mutation that makes strychnine unable to bind them but dont affect
glycine binding, consequently the person is immune to strychnine without having other
major problems such as hiperekplexia. A study of the glycine receptor subunits [29]
showed that the R131A mutation in 1 GlyRs greatly reduces strychnine binding (330fold increase in the IC50 value) without compromising receptor sensitivity to glycine.
13

Only if the colonel had this mutation, he would have survived to the poisoning.
However, the possibilities of having this exact mutation are really low as it has been
created in vitro in order to study the receptors.
From everything that has been said, we can conclude that Colonel Aureliano must have
died if he took the dose of strychnine enough to kill a horse as the book says.

Strychnine as a cardiac tonic and sleep powder

As it has been said, Nux vmica's properties are
known from ancient times in India. In Europe,
however, the first uses of strychnine (as rodencide)
date from 1640. Although strychnine lethality favored
its use as poison in many ways (as birds, rodents, cats
and dogs killer or even in tortures in the Second World
War 1), literary documents of the 19th and 20th, century
show its use as cardiac tonic (Figure 11).

Figure 11. Strychnine tonic flask

(taken from pinterest [38])

In Agatha Christie's The misterious Affair at

Styles[30], the victim, Mrs Inglethorp, seemed to
ingest a strychnine containing cardiac tonic before
going to bed. This would kill her when her husband,
Mr Inglethorp, mixed the victims sleep powder
(which contained bromide) with the tonic. That would
form a precipitate, a bromide and strychnine salt.
After the intake of the salt, Mrs Inglethorp suffered the
pertinent spasms and posterior death by strychnine
poisoning.

In this case, Mrs Inglethorp drunk the tonic as a medical treatment, to gain forces
since she was old.
Another reference to strychnine based tonics is found in The invisible man [31] by
H.G. Wells, when the protagonist ingests a strong dose of strychnine as tonic before
going to sleep. This can be seen in the following dialogue.

1 - Oskar Dirlewanger, the notorious leader of the SS Sturmbrigade Dirlewanger in the Second World
War, was known to have murdered several Jewish women by stripping them naked and having them
injected with strychnine. He and his officers then watched them convulse until death, just for their
entertainment.[34]

14

[] After a time I crawled home, took some food and a strong dose of
strychnine, and went to sleep in my clothes on my unmade bed. Strychnine is a
grand tonic, Kemp, to take the flabbiness out of a man.
It's the devil, said Kemp It's the paleolithic in a bottle.
I awoke vastly invigorated and rather irritable. You know?
I know the stuff.

From this text it can be understood that strychnine offers a better sleep and a recovery,
and it strengthens the body. This strychnine effects will be analyzed in the following
paragraphs.
Literature of the early 20th century [32]
show positive inotropic behavior
(which basically means a force
increment
of
the
muscular
contraction) of strychnine. This grants
a lengthen on the systolic period to
even the quadruple of the original
period. Also, the diastolic period is
shortened. In addition, a negative
cronotropic capacity has been listed
on strychnine (which means that
strychnine decreases heart's beating
speed) (Figure 12).

Figure 12. Cardiac rhythm changing in strychnine

administration (taken form APS [39]).

Since strychnine strengthens the heart's beat, it can be accepted that it gives forces.
For that reason, and because no accumulative effect has been detected (that is due to its
easy renal excretion), strychnine could be used has cardiac tonic. Its effect as good sleep
provider are not explained, though.
Dr Watson in Arthur Conan Doyle's The sign of four [33], when narrating some
successes that took place the night before, makes funny about his mental state at the
moment because he recommended Mr Holmes to intake grant doses of strychnine
before sleeping as muscular relaxant.
The idea of strychnine as muscular relaxant seems absurd to Dr. Watson, but it was used
as something likely by H.G.Wells. In the following paragraphs, strychnine's efficiency
as sedan or as recovering sleep provider will be studied by comparing its action
mechanism with nowadays sleep powders action mechanisms.

15

During the human's history, many sleep powders or sedans have been used. Some of
them are barbiturates, benzodiazapines and opioids. Since almost all of those relaxing
drugs share the same action mechanism, only benzodiazepines's will be explained. From
those, diazepam is also administrated in strychnine poisoning patients in order to
combat it, so his action mechanisms will be the most interesting to be explained.
Diazepam (first marketed as Valium) (Figure 13) is used
in patients that suffer from anxiety, muscle spams, panic
attacks, insomnia and epilepsy. That is because of its
hypnotic, anxiolytic, sedative and anticonvulsant effects.
Its molecular formula is 1,4-benzodiazepine.
As well as other benzodiazepines, diazepam is very
addictive and, especially if mixed with alcohol, it might
cause or deepen depressions. Its dependance is not only
physical but psychical, and it is not easy to be cured from.
What basically gives benzodiazepines their effects is their
interaction with the GABAA receptor. When attached to
benzodiazepines, GABAA experiments a transformation
in its space disposition. This is because benzodiazepines
are GABAA's allosteric modulators. As benzodiazepines
are positive allosteric modulators, they increase GABAA's
efficiency [35].

Figure 13. Diazepam formula.

(taken from inchem [40])

An allosteric modulator gets attached to the target protein by a specific point 2. The
difference between barbiturics's and benzodiazepines's action mechanism is this specific
point. Moreover, in grant doses, barbiturics can provide the same effect even without
GABA, which makes barbiturics more dangerous than benzodiazepines. (Figure 14)

Figure 14. General allosteric

mechanism. (taken from royal
society of chemistry [41]).

3 attaching points have been discoverd for benzodiazepines in GABAA receptors [35]

16

GABA (gamma-aminobutyric acid) is an amino acid (although usually the termamino

acid is only used in alfa-amino acids) which is produced by GABAergic neurons.
GABA has inhibitory functions (that will be explained later) in the SNC, and it is a
neurotransmitter. Do not confound it with GABAA.
GABAA (Figure 15) is one of GABA's receptors. GABAA is part of an ionic canal
complex which is regulated by a ligand. When attached to GABA, that ionic canal is
opened and chloride ions enter to the cell. When this happens, as explained in other
sections, the huge concentration of chloride anions produce a hyperpolarization of the
membrane, which inhibits the stimulus transmission. GABAA is very important since it
is the major inhibitory neurotransmitter receptor of mammalian central system.
The receptor is composed by 5 subunits from about 500 amino acids each other that
surround chloride ions as well as bicarbonate ions [36].

Figure 15. GABAA 3D representation (taken from bowie lab [42]).

The inhibitory action of GABAA receptor is very similar to glycine receptors. That
might be explained since glycine receptors and GABAA receptors are members of the
same family of receptors, the cys-loop ligand-gated ion channels [37]. (Figure 16)

Figure 16. Benzodiazepine's

action
mechanism
and
GABAA's hiperpolarization
function.

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The difference between diazepam and other sedans and strychnine, is that the first ones
increase its receptor's activity, which leads to the relaxation of the musculature (and the
other effects of the compounds), while strychnine inhibits its receptors, that results on
the non-inhibition of the stimulus transmission and the subsequent spams and
excitement.
For this reason, the intake of strychnine before sleeping would be contraindicated, since
it would cause nothing else than excitation and tension.
Also, that explains the successful treatment of poisoned patients with diazepam, because
it compensates the inhibition of the cys-loop ligand-gated ion channels with its
stimulation and effectiveness increase.
In conclusion, it seems to be that Dr Watson's is not only doctor by tittle but by
knowledge and formation. The ingest of strychnine before sleeping is as illogical as
drinking several cups of coffee before going bed.

Conclusion
After all the research work done in order to achieve the objectives that we initially
proposed we have been able to analyse how strychnine has been used in literature in
some specific cases. Strychnine has captivated us in the same way it attracted all authors
who have written about it and all the readers who have enjoyed their work.
We have noticed how some authors are more concerned about the scientific accuracy of
their stories than others. For instance Agatha Christie or Sherlock Holmes have proven
to write well documented stories when it comes to the substances their characters use to
commit murder.
On the other hand, we have the graphic novel Gotham by Gaslight, where can see that
even the author knew which the effects of strychnine are, he went one step further and
made strychnine the cause for Jokers grin. Another example would be the
misunderstanding from The invisible man, where the author seems to give strychnine
sleep-inducing properties, while is well known that the properties of the substance are
opposite. The last case of strychnines wrong use would be the Colonel Aureliano
Buenda and its horse-lethal dose.
Its curious to see how strychnine properties are well used on the crime novels, where
the reader really appreciates realism of stories; whereas these properties are not
correctly applied on superhero stories and science fiction novels. When reading the
latter, people dont expect scientific accuracy, just an interesting plot which can take
their mind to unexpected places. Who cares about authenticity when you have a
masterpiece on your hands?

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