Atropa belladonna L.,

Family: Solanaceae

 

 

 

Introduction

 

Atropa belladonna, commonly know as deadly nightshade,

belladonna, devil’s cherries or death cherries, belongs to the

Solanaceae family, which is also home to other well-known

plants such as tobacco and potatoes (Nicotiana and Solanum,

respectively). As implied by its common names, the toxicology

of this plant is well known and it has been used as a poison as

well as a cosmetic and anesthetic throughout its extended and

interesting tale with the human culture. This ‘femme fatale’

has been incorporated into human history since before the

Middle Ages, making a name for itself as a temptress due to

the neurological and muscarinic effects as conveyed by its

tropane alkaloids scopolamine and atropine. These drugs are

still used today as an antidote for cholinergic crises and have

been implicated in helping those with mental illnesses such as

depression and bipolar disorder. These constituents are also

responsible for the plant’s notorious use a recreational drug in

order to induce hallucinogenic episodes. The fascination with

this plant stems from its alluring appearance as well as the

mystery and taboo surrounding it.

 

Botanical Description

 

         Atropa belladonna is a large herbaceous perennial that grows to 1-1.5 m tall, rarely 2 m tall, with an erect posture.  It has a stem that ranges from purplish to green in colour and is covered in short, fine hairs. Its roots are thick, white in colour, fleshy, and 15 cm or more in length.  It has broad leaves, oval in shape, 6-20 cm long, which are alternate or in uneven opposite pairs (one leaf much larger than the other).  The often asymmetrical leaves have a smooth texture and are green in colour. The plants typically start branching at about 20-30 cm from the ground. The flowers are bell-shaped and purple with conspicuous yellow anthers. They are 2-3 cm long and grow in solitude, drooping from the axils of the leaves. The flowers usually appear between June and September, after which they produce dark, shiny black or purple berries containing sweet, dark, ink-like juices. The berries are 1.5-2 cm in diameter and are 2-celled (Blamey & Grey-Wilson 1989; Stace & Meijden undated).

 

 

Traditional Uses

 

Atropa belladonna gets its namesake from Atropos, the Fate

responsible for cutting the thread of life. This christening was

based on the plant’s dark tie to 11th century black magic,

especially related to its use in love potions and enhancing the

appearance of female allure via dilation of the pupils (Müller

1998). Witches and wizards of the olden days incorporated it

into their pharmacopeia as a flying ointment known as

‘sorcerers pomade’. This ointment included nightshade,

henbane, mandrake and hemlock mixed together and pounded

with bear grease. The ointment was then applied all over the

skin and the users claimed to experience hallucinations and

sensations of flying. Divination practices also included the

consumption of nightshade in small amounts in order to

experience visions that may foretell events to come (Lee

2007). Many superstitions surround this mystic plant,

including the placement of cuttings of the belladonna plant in

the household in order to ward off evil spirits. Conversely, the

witches and wizards took a liking to the plant because they

believed that it was a favorite of the Devil himself.

The practice of using plant extracts (particularly those from

the Solanaceae family) to dilate the eye in order to enhance

physical appeal was first recorded by Matthiolus in 1565

(Matthiolus , Feinsod 2000). This activity was recognized as

being generally dangerous, but as the doses were relatively

small, few fatalities were recorded. It was this practice of

Venetian women that lead to the discovery of the mydriatic

effects of atropine, as well as what led Linnaeus to give the

plant its species name, belladonna. This translates to

“beautiful lady” in Italian, referring to the enhanced

appearance of the women after their pupils were dilated by

drops extracted from the plant.

Pre-dating these medieval witches, A. belladonna was included

in tinctures during the Bacchanalian festivals celebrated by

the Greeks and Romans (Lee 2007). In larger doses, the plant

was indicated as a deadly poison and is thought to have made

an appearance in The Odyssey as the poison administered to

the sailors by the lovely yet malicious Circe (Campbell 2007,

Lee 2007). Tropane alkaloids have also been used to bolster

beers of the ancient world in order to give them more potent

effects upon consumption.

 

During the Roman and Byzantine empires, the drug began to

lose its tie to religious and prophetic rites and instead became

an important soporific used for medicinal purposes.

(Ramoutsaki et al. 2002). From the mid-nineteenth century

into the 1950s, A. belladonna was incorporated into plasters

and liniments for the treatment of neuralgia, chronic

rheumatism, lumbago, myalgia, pleurisy, pulmonary

tuberculosis and acute mastitis. These plasters were taken off

the market when pharmacists realized that some of them

contained extracts from monkshood (Aconitum napellus),

which produces an alkaloid called aconitine. This alkaloid was

implicated in respiratory and cardiac failures and could be

used in combination with atropine to poison people (Lee

2007).

Based on this long history of the plants use for recreational

purposes, herbalists and apothecaries began to examine the

mechanisms behind its - in some cases deadly - effects on the

body and they found that in lower doses it was useful for

medicinal purposes. Andrew Duncan of the Edinburgh

Dispensatory recommended it as a treatment for the plague as

well as nervous disorders such as epilepsy and mania (Duncan

1803). He also recorded the first use of mydriatic drugs in

ocular surgery by Professor Reimarus, an eye specialist in the

1800s. The professor used an infusion of nightshade to dilate

the pupil while he removed cataracts.

1. belladonna has had a dark and fascinating tie to European

culture ever since its first recorded use in cosmetic

applications in the 1500s (Matthiolus). It has even worked its

way into modern media in Tim Burton’s movie A Nightmare

Before Christmas. The movie featured the dried flowers

implicated in a potion used for its soporific effects. The

intrigue induced by this plant stems from its use in taboo,

sexual practices as well as the fear of its lethal properties.

Though it is dangerous to handle without proper care, this mystic past is what led to the investigation of it for medicinal

practices.

 

 

Chemistry and Pharmacology

 

The main chemical constituents of this plant include atropine

and scopolamine (Figure 2). Atropine, a tropane alkaloid, was

first isolated from Atropa belladonna in 1831 by German

pharmacist Mein (Sneader 1985). The compound exists as lhyoscyamine

in the plant and is the only active isomer, but it

isomerizes upon extraction into the dextro compound. The

racemic mixture of these two isomers is called dl-hyoscyamine

or, more commonly, atropine. Its unique tertiary-amine

structure allows penetration of the central nervous system

(CNS). It is the important characteristic of its structure that

makes it so potent as an antidote, or in cases of overdose, a

lethal poison.

Hyoscine (also called scopolamine) is another tropane alkaloid that has been isolated from A. belladonna.

Scopolamine is 10 times more potent than atropine, but it

works in the same pathway. The only difference in the

structure of the two alkaloids is in incorporation of an oxygen

atom into one of the 6-membered rings. Like atropine,

scopolamine is able to penetrate the central nervous system

(CNS) and act on the muscarinic receptors. It is interesting to

note, however, that these two compounds act only on the

muscarinic receptors and not nicotinic receptors.

 

Biological Activity

 

Atropine has significant effects on the central nervous system.

Its properties as a stereotypical anti-muscarinic xenobiotic are

well-known and given in the right dosages, it can be a vital

antidote following exposure to muscarinic agonists, such as

pilocarpine and physostigmine (Wills 1963, Greenblatt and

Shader 1973). In the 1970s, atropine was recognized as

having the ability to reverse the effects of the cholinergic crisis

as it competes with muscarinic agonists and

acetylcholinesterase inhibitors at both central and peripheral

muscarinic receptors. This activity was extremely beneficial

for military personnel, as it could mitigate the cardiac effects

of exposure to physostigmine as well as prevent the effects if

given preemptively, of up to two to three times the lethal dose

(Greenblatt and Shader 1973).

The isolation of l-atropine from A. belladonna in the 1830s

also marked an important venture into the study of

neurotransmitters in mammals, specifically the in activity of

acetylcholine and its effects in the body. It was used to map

this pathway because it allowed for a better understanding of

what effects particular neurotransmitters have on the body

(Lee 2007).

Laboratory studies on mice showed that atropine extracted

from Atropa belladonna has immuno- and gastroprotective

effects in the event of stress-induced alterations on behavior.

Although the mechanism of action was not elucidated in this

study, the authors attribute the behavioral inhibition to the

“anxiolytic-like effects” of A. belladonna (Cromwell 1943).

Studies of the effects of atropine extracted from A. belladonna

as applied to the eyes of rabbits confirmed the mechanism by

which atropine is absorbed in the iris and results in dilation of

the pupils. This is achieved by blocking the innervation to the

sphincter pupillae and ciliary (North and Kelly 1987).

Reversal of the mydriasis can take up to 10 days in humans

and can also lead to blindness and other complications when

dosed inappropriately (Salazar et al. 1976). The effect is

responsible for the plant’s use in the Middle Ages in order to

dilate the pupils for cosmetic appeal. In humans, the drug

works on the M3 muscarinic receptor on the iris sphincter

muscle. The effect is almost immediate and it extremely

powerful, lasting for 7 to 10 days depending on the

administered dose. This is due to the ease by which it is

absorbed into the body, showing a systematic absorption of up

to 65% in some cases (Howland 2011).

A review of the general effects of atropine was conducted

using 250 laboratory mice. Each of the subjects was injected

with 10μg of atropine and the resulting behaviors were then

observed. The authors noted that there was an increase in

respiration, a relaxing of the tail and the ears flattened against

the head. Increased sensitivity to touch and sound was also

noted, though the animals were fatigued for 2-3 hours after

the injection. After 24 hours, all of the symptoms had ceased

(Haley and McCormick 1957). This study was conducted as a

general survey of the effects of atropine in order to potentially

expound upon previous findings and perhaps better

understand the mechanism of action. The results of this study

have been used to further investigate the mechanisms of

action behind the atropine-induced behavioral changes.

Hyoscine has an anesthetic effect and unlike atropine, it does

not have negative effects on the electrical activity of the brain.

This was used to calm patients with mental illnesses and it

was later found useful in the treatment of major depressive

disorder and anxiety disorders. These were observed in mice

initially as a having the ability to increase “engagement” and

awareness of seemingly disinterested mice. Animal studies

such as these have been effective in the past in determining

which drugs may act on the receptors of neurotransmitters in

such a way as to regulate mood and behavior. Hyoscine is

currently undergoing clinical trials in humans with promising

results (Katz and Hersh 1981, Drevets and Furey 2010).

The primary uses of atropine and scopolamine involve its

potent effects as an anticholinergic. Its ability to work on

neurotransmitters has led to recent studies, which are looking

into its ability to alleviate the symptoms of depression as well

as inhibition of short-term memory recall (Aigner and Mishkin

1986, Drevets and Furey 2010). Its use in modern medicine

has been decreased due to the infamous cases of poisoning by

some doctors who misused their access to the drug, but it is

still an important component in opthamalic therapies.

 

 

 

 

Toxicity

Flowers of belladonna
Belladonna is one of the most toxic plants found in the Eastern Hemisphere, and its use by mouth increases risk in numerous clinical conditions, such as pregnancy, cardiovascular diseases, gastrointestinal disorders, and psychiatric disorders, among others. All parts of the plant contain tropane alkaloids.
Roots have up to 1.3%, leaves 1.2%, stalks 0.65%, flowers 0.6%, ripe berries 0.7%, and seeds 0.4% tropane alkaloids; leaves reach maximal alkaloid content when the plant is budding and flowering, roots are most poisonous in the end of the plant’s vegetation period. Belladonna nectar is transformed by bees into honey that also contains tropane alkaloids. The berries pose the greatest danger to children because they look attractive and have a somewhat sweet taste. The root of the plant is generally the most toxic part, though this can vary from one specimen to another.

The active agents in belladonna, atropine, hyoscine (scopolamine), and hyoscyamine, have anticholinergic properties.The symptoms of belladonna poisoning include dilated pupils, sensitivity to light, blurred vision, tachycardia, loss of balance, staggering, headache, rash, flushing, severely dry mouth and throat, slurred speech, urinary retention, constipation, confusion, hallucinations, delirium, and convulsions. In 2009, A. belladonna berries were mistaken for blueberries by an adult woman; the six berries she ate were documented to result in severe anticholinergic syndrome. The plant's deadly symptoms are caused by atropine's disruption of the parasympathetic nervous system's ability to regulate involuntary activities, such as sweating, breathing, and heart rate. The antidote for belladonna poisoning is physostigmine or pilocarpine, the same as for atropine.

Atropa belladonna is also toxic to many domestic animals, causing narcosis and paralysis. However, cattle and rabbits eat the plant seemingly without suffering harmful effects. In humans, its anticholinergic properties will cause the disruption of cognitive capacities, such as memory and learning.

 

Medicinal uses

Scientific evidence to recommend the use of A. belladonna in its natural form for any condition is insufficient, although some of its components, in particular l-atropine, which was purified from belladonna in the 1830s, have accepted medical uses. Donnatal is a prescription pharmaceutical, approved in the United States by the FDA, that combines natural belladonna alkaloids in a specific, fixed ratio with phenobarbital to provide peripheral anticholinergic/antispasmodic action and mild sedation. According to its labeling, it is possibly effective for use as adjunctive therapy in the treatment of irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis.

 

Belladonna has been used in herbal medicine for centuries as a pain reliever, muscle relaxer, and anti-inflammatory, and to treat menstrual problems, peptic ulcer disease, histaminic reaction, and motion sickness. At least one 19th-century eclectic medicine journal explained how to prepare a belladonna tincture for direct administration to patients.

 

Belladonna tinctures, decoctions, and powders, as well as alkaloid salt mixtures, are still produced for pharmaceutical use, and these are often standardised at 1037 parts hyoscyamine to 194 parts atropine and 65 parts scopolamine.[citation needed] The alkaloids are compounded with phenobarbital and/or kaolin and pectin for use in various functional gastrointestinal disorders. The tincture, used for identical purposes, remains in most pharmacopoeias, with a similar tincture of Datura stramonium having been in the US Pharmacopoeia at least until the late 1930s. Cigarettes with belladonna leaves soaked in opium tincture were a prescription medicine as recently as 1930. The combination of belladonna and opium, in powder, tincture, or alkaloid form, is particularly useful by mouth or as a suppository for diarrhoea and some forms of visceral pain; it can be made by a compounding pharmacist, and may be available as a manufactured fixed combination product in some countries (e.g., B&O Supprettes).

 

Scopolamine is used as the hydrobromide salt for GI complaints and motion sickness, and to potentiate the analgesic and anxiolytic effects of opioid analgesics. It was formerly used in a painkiller called "twilight sleep" in childbirth.

 

Atropine sulphate is used as a mydriatic and cycloplegic for eye examinations. It is also used as an antidote to organophosphate and carbamate poisoning, and is loaded in an autoinjector for use in case of a nerve gas attack. Atropinisation (administration of a sufficient dose to block nerve gas effects) results in 100 percent blockade of the muscarinic acetylcholine receptors, and atropine sulphate is the benchmark for measuring the power of anticholinergic drugs.

 

Hyoscyamine is used as the sulphate or hydrobromide for GI problems and Parkinson's disease. Its side-effect profile is intermediate to those of atropine and scopolamine, and can also be used to combat the toxic effects of organophosphates. Hyoscyamine was the primary alkaloid in Asthmador, a nonpresciption treatment for the relief of bronchial asthma, until Asthmador was discontinued.

 

Alternative medicine

Belladonna preparations are used in homeopathy as alternative medicine treatments for various conditions. In homeopathic practices, belladonna was prescribed by German physician, Samuel Hahnemann, as a topical medication for inflammation and pain. In the form of Doktor Koster's Antigaspills, belladonna was a homeopathic medication for upset stomach and excessive flatulence. There is insufficient scientific evidence justifying the use of belladonna for these or any other clinical disorders

 

In one study, the most common preparation was diluted to the 30C level in homeopathic notation. This level of dilution does not contain any of the original plant, although preparations with lesser dilutions that contain trace amounts of belladonna may exist. In 2010 and again in 2016, the US Food and Drug Administration warned against the use of homeopathic teething tablets found to contain belladonna.

 

Clinical Studies

 

The most common symptoms of A. belladonna poisoning are

tachycardia and mydriasis, as indicated by the anticholinergic

effects of the drug. Other observed symptoms include increase

in body temperature, flushing of the face, repressed salivation,

bizarre mental state described as manic and paralysis of the

detrusor muscle of the bladder, resulting in urine retention

(Lee 2007).

Most studies of the effects of A. belladonna on humans come

from toxicology reports wherein the plant was accidentally

ingested and the symptoms were severe enough to warrant

medical attention. The amount ingested from eating the

berries, which are sometime mistaken for blackberries, was

not enough to kill any of the 23 children in the reported cases.

Common symptoms of belladonna intoxication include

meaningless speech, tachycardia, mydriasis, and flushing. In

some cases the anticholinergic effects were so severe that

physostigmine had to be administered to restore homeostasis

(Çaksen et al. 2003).

Scopolamine was administered transdermally to 16 patients

with nausea induced by calorization of the ear in a

randomized, double blind study. Nausea was reduced

significantly compared to the effects of the placebo and it was

also noted that introduction of scopolamine into the body 6 to

8 hours before exposure to a known motion sicknessinducing

stimulus will prevent the onset of symptoms. Side

effects were negligible (Pyykkö et al. 1985).

One of the most important uses of atropine came about during

the 1930s and 40s when OP insecticides that were later developed into nerve agents in chemical warfare due to their

ability to inhibit acetylcholinesterase. Upon exposure to these

agents, one would experience increased levels of

acetylcholine, as the enzyme to metabolize it was no longer

functioning due to inhibition. Atropine was then administered

due to its muscarinic antagonist effects and it worked

effectively and in small enough doses to be safe (Howland

2011).

Few clinical studies have been conducted using these drugs

due to the well-known cases of poisoning and the generally

infamy the plant has earned throughout its long, dark history.

The most recent interest with these muscarinic antagonists

comes in the field of mental health, where a new theory is

circulating that Alzheimer’s and dementia may be related to

the cholinergic system. Scopolamine has been used to induce

short-term memory inhibition in order to help elucidate the

mechanism by which dementia develops. (Aigner and Mishkin

1986). This new field has shown some promising results and

may potentially provide just retribution for atropine and

scopolamine and import and effective treatments in western

medicine.

 

Contraindications

 

Allergic reactions to topical application of atropine have been

described as causing swelling of the eyelids, followed by itchy

and stinging sensations. In patients who are prone to

developing narrow angle glaucoma, application of the drug

can lead to an acute attack, but this risk has been evaluated as

minuscule.

‘Hot as a hare, blind as a bat, dry as a bone, red as beet and

mad as a hen’ was an aphorism widely used to describe the

symptoms of belladonna poisoning. These symptoms are fairly

unique to the effects of this particular plant, but can

sometimes be confused with other plant poisons in the

Solanaceae family, such as henbane (Hyoscyamus niger).

Dilation of the eyes, as induced by atropine, results in

photophobia until the pupils return to their normal

circumference, which is usually no longer than a few hours.

Dryness of the skin, mouth and throat can occur due to

decreased secretion from the mucous membranes.

Restlessness, irritability or delirium can also occur, as

atropine stimulates the central nervous system. Use of

atropine for any condition in elderly patients is not

recommended, as it can cause confusion and may cause brain

damage. Fatalities, though rare, can occur upon ingestion of

this drug due to depression of circulatory and respiratory

functions. This is more dangerous in children than adults, as

the fatal dose in children is 10mg versus 100mg (North and

Kelly 1987). 90-130 mg is considered to be a toxic dose (Lee

2007). Death is rare in the modern age because the symptoms

are so well known and a cleansing of the stomach as well as

use of artificial ventilation and diazepam can control

convulsions and reduce the risk of mortality. In most cases,

atropine is eliminated from the body in 72 to 96 hours

without lasting effects on the patient.

When atropine was first isolated and brought to the medical

market the medicinal knowledge about the drug’s effects was

incomplete. The plasters and eye drops could be incorrectly

prepared and as a result, many accidental deaths occurred

These treatments have since been

banned from the market. Atropine can also be absorbed

through the GI tract, so if an animal consumes the berries and

the meat from said animal is ingested by a human, it can cause

unusual and sometimes toxic symptoms (Polson et al. 1983).

One of the most notorious incidences of atropine poisoning

was the attempted murder of Mrs. Agutter by her husband in 1994. By the 1990s, atropine was only available for the use of

physicians and nurses, so it was relatively easy for him to

acquire as he worked in a hospital. Dr. Agutter served his wife

a gin and tonic laced with atropine, as the quinine in the tonic

water disguised the bitter taste. Within five minutes she felt

an agonizing pain in her throat and she started to experience

hallucinations. It was later found that she had only consumed

50mg of atropine before the symptoms hit and she stopped

drinking. Due to her husband’s miscalculations, she survived

and he was found guilty of attempted murder and spent the

next twelve years in prison (Lee 2007).

 

Current Use in Allopathic and CAM Therapies

 

Atropine sulfate drops are one the main therapies prescribed

for the treatment of amblyopia, a condition of the eye that can

lead to vision impairment. A clinical study evaluating the

efficacy of the atropine drops over a 6-month and two year

period showing 49% improvement in the condition of the

affected eye (Repka et al. 2005). Atropine can be administered

via oral, inhalation and intramuscular routes and it can last for

24 hours within the body depending on the dose. When given

a 2mg dose via autoinjector, heart rate increased to maximal

level in 16 minutes. These autoinjectors are used as an

immediate response for terrorist attacks, especially when they

involve exposure to nerve gas. The atropine stops muscle

spasms and allows heart rate to return to normal (Howland

2011).

Atropa belladonna is commonly used to combat local

inflammation that, if untreated, can lead to sepsis and death. A

study on the various homeopathic remedies that used A.

belladonna outlines the major drug used in homeopathic

treatment of infection. These include Belladonna—Injeel®,

Belladonna—Injeel Forte® and Belladonna Homaccord®.

Preparations containing A. belladonna constituents were

effective in regulating what types of cells migrate during the

inflammatory process. This activity helps lower the presence

of proteolytic enzymes, free radicals and chemical mediators

that may infer with the immune processes (Pedalino et al.

2004). Another medicinal use of atropine is to lower blood

pressure via competition for the norepinephrine receptor,

thus mitigating the effects of hypertension (Abraham et al.

1981).

Hyoscine is currently undergoing clinical trials as a treatment

for major depressive disorder. Its efficacy in relieving

symptoms of depression relative to the effect of placebo is

promising and the efficacy improves with continuous dosing.

The mechanism of action is currently unknown, but the late

onset of the antidepressant effects (past the time of the

anticholinergic effects) suggest that the drug may work on

transcription of later onset genes as opposed to working on

the muscarinic receptors (Drevets and Furey 2010). This

alkaloid has also been found to alleviate motion sickness.