Deadly Cures: Medical discoveries from poisonous plants Cassandra L. Quave, Ph.D. Assistant Professor Department of Dermatology (SOM) Center for the Study of Human Health (ECAS) Curator Emory University Herbarium E-mail: cquave@emory.edu Website: http://etnobotanica.us/ Twitter: @QuaveEthnobot Deadly Nightshade

Virtue itself turns to vice, being misapplied,

And vice sometimes by action dignified.

Within the infant rind of this small flower,

Poison hath residence, and medicine power.

-William Shakespeare, Romeo and Juliet

Outline

• Medical Ethnobotany

• Why do plants make poisons?

• Poison… or food?

• Poisons in history, legend and myth

• Medical discoveries from poisonous plants

• Poisonous plants in the home and yard

The Science of Ethnobotany

• Ethnobotany (from

ethnology, study of

culture, and botany, study

of plants) is the scientific

study of the relationships

that exist between

peoples and plants.

• Ethnobotany is the

science of survival.

Ethnobotany is Multidisciplinary

Ethnobotany

Botany

Chemistry

Microbiology

Anthropology

Linguistics

Pharmacology

• Medicine • Conservation • Food security

Deter other plant species from growing nearby

Fight off microbial invasion & infection

Attract pollinators Defense against herbivory

Why do plants make poisons?

Poisons in Human History

• Early humans likely experienced much poisoning in the search for new foods

• One function of early agriculture was to select for more palatable (less bitter, less poisonous) plant variants

• Food processing to remove poison also important

Cassava

Cassava: Sweet and Bitter Manioc

• Manihot esculenta Crantz, Euphorbiaceae ▫ Starchy tuber is the main source

of carbohydrates in the tropics

▫ Tuber is filled with poisonous cyanogenic glycosides and hydrogen cyanide (HCN)

A dose 40 mg of pure cassava cyanogenic glycoside is sufficient to kill a cow.

▫ Tuber is processed to remove the poison (soaking, boiling, fermentation)

Drinking masato – fermented cassava beverage. Peruvian Amazon

Poke Weed…

Poison, Medicine or Food?

• Phytolacca americana L., Phytolaccaceae Young plant (young leaves only) eaten as “poke salet”

• Contains phytoagglutinins (pokeweed mitogens), but can be denatured with processing (heat labile) ▫ Boiled in water, water tossed several times

(thrice boiled)

• Used in Native American traditional remedies for ulcer, rheumatism, kidney problems

• Mature plants (esp. roots) are highly toxic if consumed.

• Symptoms include: ▫ convulsions, diarrhea, headache, seizures, rapid

pulse, difficulty breathing, stomach pains, vomiting, weakness

Poisonous Gymnosperms • All cycads and zamias have poisonous fleshy seeds

▫ BUT… if the azoxy alkaloids are washed out, they can be eaten (or flour made from them), as was common practice among the Seminole tribe of Florida

Fern palm

Cycas circinalis L.,

Cycadaceae

False sago palm

Dioon edule

Lindl.Zamiaceae

Coontie

Zamia integrifolia L. f.,

Zamiaceae

Poisons and the Criminal Arts

• Agrippina (19-59 AD) ▫ Empress and wife of Emperor

Claudius and mother of Nero

▫ Used poisonous mushrooms to kill Lollia Paulina, Marcus Sianus, and her husband Claudius, among others

The execution of Socrates – Plato’s account

Socrates walked about, and presently, saying that his legs

were heavy, lay down on his back--that was what the

man recommended. The man--he was the same one who

had administered the poison--kept his hand upon

Socrates, and after a little while examined his feet and

legs, then pinched his foot hard and asked if he felt it.

Socrates said no. Then he did the same to his legs, and

moving gradually upward in this way let us see that he

was getting cold and numb. Presently he felt him again

and said that when it reached the heart, Socrates would

be gone.

The coldness was spreading about as far as his waist

when Socrates uncovered his face, for he had covered it

up, and said--they were his last words--Crito, we ought

to offer a cock to Asclepius. See to it, and don't forget.

Poison Hemlock Conium maculatum L., Apiaceae

• European poison hemlock made famous by Socrates’ execution (contains toxic pyridine alkaloids)

• Active Compound:

▫ Cicutoxin, in root and above-ground parts: is a violent convulsant that acts directly on the central nervous system

• Symptoms:

▫ 2-3 cm section of root can kill an adult

Medicine or Poison?

The distinction between poison and medicine often comes down to two simple points: dose and intent.

“Natural” does not always = safe!!

Poisons and the criminal arts • Cleopatra (51-30 BC)

• Tested poisons on her slaves ▫ Henbane

Hyoscyamus niger L., Solanaceae

▫ Belladonna; Deadly nightshade

Atropa belladonna L., Solanaceae

▫ Poison nut

Strychnos nux-vomica L., Loganiaceae

Deadly Nightshade Atropa belladonna L., Solanaceae

• It was used in traditional treatments for centuries for an assortment of conditions including ▫ Headache

▫ Menstrual symptoms

▫ Peptic ulcer disease

▫ Inflammation

▫ Motion sickness

▫ Mydriatic (pupil dilator)

• Plant occasionally used as a recreational drug because of the vivid hallucinations and delirium that it produces. ▫ Unpleasant hallucinations. Recreational use is

considered extremely dangerous because of the high risk of unintentional fatal overdose.

▫ The CNS effects of atropine include memory disruption, which may lead to severe confusion

Deadly Nightshade Atropa belladonna L., Solanaceae

• Toxicity

▫ Berries are attractive & taste sweet, but

consumption can be fatal, esp. in

children

▫ Anti-cholinergic

▫ Symptoms 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

Deadly Nightshade

Atropa belladonna L., Solanaceae

• Source of atropine ▫ Useful in management of

bradycardia following a myocardial infarction

▫ Used in management of hypotension that is associated with slow heart rate

▫ Eyedrops or ointment to open iris for eye exams, surgical procedures, and to treat anterior uveitis

▫ Antidote for cholinergic crisis (such as induced by physostigmine or nerve gas)

• Source of hyoscamine and scopolamine – used in functional gastric disorders

Poison nut Strychnos nux-vomica L., Loganiaceae

• Active Compound: ▫ Indole alkaloids (strychnine

and brucine) from dried ripe seeds; all parts contain strychnine

• Symptoms: ▫ Agitation, muscle spasms,

convulsions

▫ Extremely toxic, strychnine is fatal to humans at doses of 60-90 mg

Henbane Hyoscyamus niger L., Solanaceae

• Traditionally used in combination

with Atropa belladonna and Datura spp. for pyschoactive effects (hallucinogen) in witches’ brew

• Source of hyoscamine and scopolamine

• Toxicity:

▫ Symptoms include hallucinations, dilated pupils, restlessness and flushed skin

Scopolamine/Hyoscine Hyoscamine

Jimsonweed Datura stramonium L., Solanaceae

• Used as recreational psychoactive drug – users often unaware of toxicity/poisonous nature of plant

• Active Compound: ▫ Scopalamine: most found in leaves,

unripe capsules, especially seeds

• Symptoms: ▫ Even small amounts fatal;

symptoms similar to Atropa belladonna (anti-cholinergic; flushed skin, dilated pupils, dry mouth, delirium, death from respiratory failure)

Scopolamine (aka Hyoscine) • Medicinal applications:

▫ Remedy for motion sickness

Oral dose or by patch

▫ Postoperative nausea/vomiting

▫ Gastrointestinal spasms

• Toxicity:

▫ Symptoms include: tachycardia, arrhythmia, blurred vision, photophobia, urinary retention, dry mouth, skin reddening

• Overdose/poisoning can be treated with physostigmine, a plant compound from the Calabar bean (Physostigma venenosum)

Hyoscyamine

• Medicinal uses:

▫ Treatment of certain GI disorders (peptic ulcers, irritable bowel syndrome, colic) and control some of the symptoms of Parkinson’s disease

• Toxicity

▫ Symptoms include headache, nausea, vomiting, disorientation, hallucinations, euphoria, sexual arousal and short-term memory loss

Calabar bean Physostigma venenosum Balf. f., Fabaceae

• Calabar bean ▫ Historical ‘ordeal’ bean in the Calabar area

of Nigeria

▫ Given to people on trial – if died, were guilty, if vomit & live, not guilty

• Physostigmine ▫ Medicinal uses: myasthenia gravis,

glaucoma, Alzheimer's disease and delayed gastric emptying

▫ Antidote of choice for Datura stramonium & Atropa belladonna poisoning

▫ Toxicity: cholinergic syndrome (SLUDGE: salivation, lacrimation, urination, defecation, gastrointestinal upset, vomiting)

Poisons in Mythology • Plant teratogen causes Cyclopia!

• Veratrum album L., V. californicum Durand and V. viride Aiton, Melanthiaceae [false hellebore] – case of mistaken identity with other hellebore (Helleborus spp., Ranunculaceae) used in ancient Greek medicine as purgative

• Consumption during early pregnancy (in humans and other animals – esp. common in sheep) results in cyclopia ▫ Single eye, often missing nose

▫ Usually stillborn

• Responsible compound: cyclopamine

False Hellebore/ White Hellebore

Veratrum album L., Melanthiaceae

Hellebore/ Black Hellebore

Helleborus niger L.

Ranunculaceae

Groundsels; Ragworts Senecio spp., Asteraceae

• Mistaken identity – confused with a Gnaphalium spp.& included in herbal remedy for colds

• Active Compound:

▫ Hepatotoxic pyrrolizidine alkaloids

• Symptoms:

▫ Ingestion results in acute illness and death in livestock and humans

Senecio flaccidus L. (Hook)

Oleander Nerium oleander L., Apocynaceae

• Examples of poisoning events: ▫ Ingestion after confusion

with eucalyptus ▫ Ingestion by children ▫ Suicide attempts

• Active Compound: ▫ Cardioactive glycosides;

oleandrin is the main glycoside from leaves

• Symptoms: ▫ Ingestion results severe

vomiting, bloody diarrhea, irregular heartbeat, drowsiness, unconciousness, respiratory paraylysis, fatal

Advisory Council, Zayed Complex for Herbal Research and

Traditional Medicine, Abu Dhabi, UAE

Ginkgo: Poison or Medicine? Both? • Ginkgo biloba L., Ginkgoaceae • Leaves used in herbal supplements for improved cognitive function • Seeds contain a neurotoxin:

▫ 4-O-methyl pyridoxine (ginkgotoxin) Interferes with amino acid metabolism Results in convulsions and death (27% lethality)

▫ Fruit pulp causes allergic contact dermatitis

Hortus Botanicus in Leiden, The Netherlands. Oldest Ginkgo in Europe. Ginkgo fruits

Autumn crocus; Meadow saffron Colchicum autumnale L., Colchicaceae

• Colchicine derived from this plant used medicinally to treat gouty arthritis

• Active Compound: ▫ Colchicine & other alkaloids

▫ Highest concentration is in seeds and corm

Amount of colchicine in 2-3 seeds can kill

• Poisoning Symptoms: ▫ Burning of throat & stomach,

vomiting, purging, weak-quick pulse, kidney failure, respiratory failure, often fatal, flowers have been fatal to children

Colchicine

• 1st isolated in 1820

• Used as alternative gout treatment for those unable to tolerate NSAIDs

• How it works: it inhibits deposition of uric acid (urate crystals), raises tissue pH by inhibiting glucose oxidation, reducing production of lactic acid in leukocytes • Plant extract not used because colchicine is highly toxic, and

dose must be controlled

• History

▫ 1st described by Dioscorides as a gout treatment in De Materia Medica

▫ Used in ancient Islamic medicine & in Europe; Benjamin Franklin in USA used it to treat his gout

▫ 2009 – FDA approved for gout treatment Colchicum autumnale

(Colchicaceae)

Pain of gout

Draining of dropsical fluid, 1741 Digitalis purpurea L.

Common Foxglove

Foxglove Digitalis purpurea L., Plantaginaceae

• 1700’s British folk medicine

• William Withering published book in 1785 based on the accounts of an “old woman in Shropshire”

• Used in treatment of dropsy

• Still used for congestive heart failure

• Led to discovery of digitoxin and digoxin, found in leaves, seeds and flowers

• Toxicity: therapeutic dose is close to the toxic dose ▫ Poisoning can occur from the plant or

overdose of medication

▫ Death from Digitalis poisoning from ventricular fibrillation

▫ Side effects: nausea, fatigue, salivation, severe headache, irregular heartbeat and pulse, toxicity in combo with calcium, sudden death

Digitoxin

Digoxin

Pacific Yew Taxus brevifolia Nutt., Taxaceae

• History of use in Native American traditional

medicine: respiratory, dermatological, gastrointestinal, and urological applications

• Toxicity: • Taxines are cardiotoxic • Lethal dose: 4-20 mg/kg • Rapid absorption from GI tract to circulatory system • Affects sodium-potassium transport • Sudden death occurs with trembling, labored

breathing, and collapse • Most deaths in animals that forage on leaves, human

deaths rare

• Taxol (Paclitaxel) ▫ Taxane diterpene discovered in 1960s NCI screen

Showed strong activity against solid tumors, melanoma, and leukemia models

Taxol concentations are low; most toxicity attributed to the taxines

▫ It took 30+ years from discovery to approval Paclitaxel

• One BIG problem – very low yield in plant (0.004%) ▫ Solution: semi-synthesis of taxol by

conversion of metabolites available in larger quantities in needles of English Yew (Taxus baccata)

Needles were a renewable source – no need to kill the tree by removing bark

• Taxol (Bristol Meyers Squibb) approved in USA in 1993 ▫ Treatment for ovarian cancer

and secondary treatment for breast and non-small cell lung cancers

• Docetaxel was approved in 1995 ▫ marketed as Taxotere

▫ more water soluble than taxol Breast and ovarian cancer

• Abraxane – paclitaxel bound to albumin, approved in 2005 ▫ Breast cancer unresponsive to

other chemotherapies Taxus baccata (Taxaceae) – English Yew

Taxol

Docetaxel (Taxotere®)

• Semi-synthetic analogue of paclitaxel

• Anti-mitotic chemotherapy (interferes with cell division)

• FDA approved for: ▫ locally advanced or metastatic breast

cancer, head and neck cancer, gastric cancer, hormone-refractory prostate cancer and non small-cell lung cancer

▫ Maybe used alone or in drug combos

• Disadvantage: prone to cellular drug resistance

• Side effects: ▫ Alopecia, neutropenia, anemia

Mayapple; American Mandrake Podophyllum peltatum L., Berberidaceae

• Long history of traditional use of rhizomes as medicine by Native Americans ▫ Dried & made into powder, then

eaten or drunk as laxative or antihelmintic

poultice applied to warts & skin growths

• Currently plant extracts used as topical treatment for warts & skin growths

• Toxicity: ▫ Fruits are poisonous if eaten in large

amounts. Leaves and roots poisonous if consumed. Podophyllotoxin (medicinal compound) is poisonous if taken internally.

Etoposide

• Marketed as VePesid®

▫ Small cell lung cancer, testicular cancer & lymphomas

• antineoplastic or cytotoxic chemotherapy drug

• It is a semisynthetic derivative of podophyllotoxin used in the treatment of certain cancers: ▫ Testicular, bladder, prostate, lung, stomach, and uterine,

cancers. Hodgkin's and non-Hodgkin's lymphoma, mycosis fungoides, Kaposi's sarcoma, Wilm's tumor, rhabdomyosarcoma, Ewing's sarcoma, neuroblastoma, brain tumors

• Administered orally

• Side Effects: ▫ Low white blood cell count, Low platelet count, Hair loss ,

Menopause, Loss of fertility, Nausea and vomiting, Low blood pressure

Teniposide • Teniposide marketed as Vumon®

brain tumors, childhood acute leukemia

• Administered by injection

• Semisynthetic derivative of podophyllotoxin ▫ Used in combination with other approved

anticancer agents for induction therapy in patients with refractory childhood acute lymphoblastic leukemia.

• Side-Effects ▫ Severe myelosuppression with resulting

infection or bleeding may occur; hypersensitivity reactions

(+)-Tubocurarine

Dart Poisons

The varzea

Dart Poisons

• Neuromuscular blocking agents ▫ Isoquinoline & indole alkaloids

▫ (+)-tubocurarine leading agent

▫ Competes with acetylcholine for cholinergic receptors at the motor endplate, preventing formation of action potential

▫ Causes death by paralyzing the respiratory system, causing asphyxiation

• Loganiaceae & Menispermiaceae families are primary plant sources ▫ Strychnos spp. (Loganiaceae)

▫ Chondrodendron tomentosum Ruiz & Pav., Menispermiaceae (curare vine)

Chondrodendron tomentosum

Curare vine Chondrodendron tomentosum Ruiz & Pav., Menispermiaceae

• (+)-Tubocurarine ▫ Skeletal muscle relaxant

▫ Helped to revolutionize surgery – less anesthesia was necessary to perform operations

▫ Acts as a long-duration, non-depolarizing neuromuscular blocking agent that is a competitive antagonist of nicotinic neuromuscular acetylcholine receptors

▫ Rarely used today as an adjunct for clinical anesthesia because safer alternatives such as cisatracurium and rocuronium are available.

Useful poisonous plants in the Mediterranean

Pantelleria

Basket weaving for Agricultural & Fishing Tools

Euphorbiaceae

Daphne gnidium L., Thymelaeaceae

Ethnobotanicals uses: • Insect repellent (ticks and

fleas) • Hemostatic

Daphne gnidium poisoning

• Leaves are the most toxic

• Symptoms include: ▫ Headache

▫ Shivering

▫ Paleness

▫ Pupil dilatation

▫ Mouth and lips swelling

▫ Diarrhea and digestive spasms

▫ Convulsion

▫ Pulmonary disorders

▫ Death

Castor bean Ricinus communis L., Euphorbiaceae

• Castor oil extracted from seeds is used medicinally as laxative – but eating the seeds can kill

• Active Compound: ▫ Ricin: a highly poisonous

phytotoxin (plant protein)

▫ FBI lists ricin as the 3rd most poisonous substance known 3,000 x more toxic than cyanide

12,000 x more toxic than rattlesnake venom

• Toxicity: ▫ Symptoms include nausea,

muscle spasms, purgation, convulsions, and death (accompanied by hemorrhage, GI edema and degeneration of kidneys)

Poisonous plants in the home and yard

Calcium oxalate is found in many

house plants • Symptoms of poisoning:

▫ Dermatitis

▫ Swelling of the tongue, can lead to asphyxiation

▫ Irritation/burning in the mouth

▫ Development of kidney stones (edible plants i.e. Rumex spp., dock)

▫ Toxic to humans and pets

Poisonous house plants from the

Araceae family contain calcium oxalate

Philodendron Philodendron spp.

Dumbcane Dieffenbachia maculata

Caladium; Elephant Ear Caladium spp.

Abrus precatorius L., Fabaceae (rosary pea;

jequirity bean) • Toxic effect from chewing the seeds

• Active Compound:

▫ Abrin (phytotoxin similar to ricin) & abric acid from thoroughly chewed seeds

• Symptoms:

▫ Gastrointestinal distress

▫ Fatal to humans and animals

Rhus Dermatitis

• Rhus = group of plants responsible for more cases of Allergic Contact Dermatitis (ACD) than any other allergen

• Rhus is the botanical synonym for Toxicodendron in the Anacardiaceae family

• Pentadecylcatechol is an allergin found in the plant sap (oleoresin)

Poison ivy

Poison oak

Poison sumac

Mango (rind)

Lacquer tree

Cashew nut

Indian marking nut

Rhus Dermatitis Plants • Anacardiaceae

▫ Toxicodendron radicans (L.) Kuntze [Poison Ivy]

▫ Toxicodendron diversilobum (Torr. & A. Gray) Greene [Poison Oak]

▫ Toxicodendron vernix (L.) Kuntze [Poison Sumac]

▫ Mangifera spp. [Mango]

Rhus Dermatitis Plants • Anacardiaceae

▫ Toxicodendron vernicifluum (Stokes) F.A. Barkley [Lacquer Tree]

▫ Anacardium occidentale L. [Cashew Nut]

▫ Semecarpus anacardium L. f. [Indian marking nut]

Conclusions

• There are many poisonous plants that actually serve an important role to many in terms of: ▫ Food security

▫ Medicine

▫ Fishing tools

▫ Hunting tools

• Poisonous chemicals can be concentrated in specific plant tissues

• In most cases, there is a thin line between poison and medicine and it all comes down to 2 key factors: dose and intent.

Acknowledgements • Emory University Herbarium

Staff and Volunteers

• Philanthropic donation

• How to help the Emory Herbarium:

▫ Support our educational outreach and research mission! We are seeking donations of funds, books, ethnobotanical objects, and historic herbaria collections. Visit our website for more info: https://scholarblogs.emory.edu/emoryherbarium/