BOT 380 Hallucinogens - Anticancer

Psychoactive plants

Psychoactive plants

Contains compounds that affect the mind or alter the state of consciousness

• stimulants

• Hallucinogens

• Analgesics

• Sedatives

• Hypnotics

• Narcotics

Hallucinogenic Plants

all distort the perception of reality

• experience of a dream world

• Alter idea of time, space, sound, touch, smell, taste, colour

• Affect cognition and moods

Confusions, memory loss, or disorientation rarely occur

Hallucinogen definition

Any agent that causes alterations in perception, cognition, and mood as its primary psychobiological actions in the presence of an otherwise clear sensorium

Psychedelic Greek meaning

Mind manifesting or mind expanding

Psychotomimetics

• ‘induce psychotic states’

• Compared to symptoms of schizophrenia

Traditional use of hallucinogenic plants

• Used worldwide but indigenous peoples for magic, medical,a do religious purposes

• Used to mediate between man and the supernatural

Albert Hofmann

1949 - interest increases with the synthesis of LSD

Psychoplastogen

Small molecules that produce rapid and sustained structural and functional neural plasticity that are considered therapeutics for depression, addiction and PTSD

ex. Ketamine, MDMA, Scopolomine, LSD, psilocin

MDMA

In conjunction with psychotherapy for PTSD, anxiety and eating disorders

Psilocybin

For treatment of a variety of disorders including anxiety and depression

Use of LSD

cluster headaches and anxiety

Ibogaine

Anti addiction properties

What are monoamine (adrenergic) hallucinogens

Indole and catechol hallucinogens

Indole and catechol hallucinogens properties

• target serotonin related pathways

• Vivid sensory effects

• Perception is altered while maintaining contact with real world

• Low toxicity

What type of chemical is indole

Alkaloid with indole component

Sources and compounds of indole

Fungi

• Claviceps purpurea (Ergot alkaloids)

• Psilocybe mexicana (Psilocybin)

Plant

• Turbina corymbosa (lysergic acid)

Claviceps purpurea - Ergot

• Parasitic fungus

• Fungal spores grow hyphae into ovaries of grain to obtain nutrients

Ergotism

• Results from eating infected grain

• Symptoms: gangrene,nervous spasms, psychotic delusions, convulsions

Salem witch trials

• 1692

• Maybe have resulted from outbreak of Ergotism

• Suggests that the ‘Great Fear’ of peasant revolt in 1789 France where many ‘lost their heads’ may have

  occurred due to ingestion of ‘bad flour’

Ergot compounds

*derived from ergoline

• ergotamine

• Ergine

• Lysergic acid

Effects of chemical compounds of Ergot

Show both antagonist and agonist effects of serotonin, dopamine, and adrenergic receptors

Modern uses of Ergot compounds

• Uterine contractions

• Treats migraines

• Reduce prolactin levels resulting from pituitary tumours

• Reduce postpartum hemorrhage

• Treat senility and Alzheimer’s dementia

What is LSD

d-lysergic acid diethylamide

• synthetic compound derived from Ergoloids

• Acts as a model for plant derived psychedelics mechanism of action

Effects of LSD

• small dose intensify perception

• Large dose causes hallucinations

• Rapid and complete tolerance develops for behavioural effects after 4-7 days, lasts for 3 days

• Not reinforcing (addictive) like other drugs and does not produce withdrawal symptoms

• Massive overdose required for lethal effects

LSD mechanism of action

• Regulate serotonin pathways

• LSD binds to multiple serotonin receptor subtypes (5HT receptors)

• Has both agonist and antagonist effects

• Tolerance due to down regulation of certain serotonin receptor

LSD: Good Trip

• profound perceptual distortions and hallucination

• Heightened awareness of sensations and altered sense of self

• Effects highly variable

LSD: Bad Trip

• panic episode brought on by dislike of drugs effect and fears that the experience will not end

• Flashbacks - hallucinogen persisting perception disorders

What is this compound?

serotonin

Morning Glories

• Turbina produces seeds called ‘Ololiuqui’ (round object)

• contains lysergic acid

Where is lysergic acid found in morning glories

Lysergic acid alkaloids are found in these seeds

Psilocybe species: ‘psychedelic mushrooms’ history

• religious ceremonies

• Mexico and Central America

• called Teonanacatl (God’s flesh)

Richard Evans Schultes

First botanist to record rituals and beliefs surrounding this sacred mushroom

Hallucinogenic compounds of Psilocybe mushrooms

• structurally similar to serotonin

• effects similar to lysergic acid and LSD

Timothy Leary

• 1960s

• invested effects of eating magic mushrooms

What is this compound?

Psilocybin

Effects of Psilocybe compounds

Timeline of effects

• Dizziness, weakness and twitching (30 mins after ingestion)

• Visual effects seen (30-60 min after)

• Normalcy returns (180 mins after)

Peyote Cactus

Lophophora williamsii

Peyote

• small spineless cactus

• >56 different alkaloids identified

• mescaline is the primary psychoactive alkaloid

Pharmacology of mescaline

• similar to indole hallucinogens

• contains catechol group

• readily absorbed by body

Psychoactive dose of mescaline

• Dilation of pupils

• Increase in pulse rate and blood pressure

• Elevation of body temperaturewas

What is this compound

Catechol

Mechanism of action of catechol

• Mescaline resembles catecholamine neurotransmitters norepinephrine and dopamine

• Effects suggested to mirror mechanism of indole hallucinogens via serotonin actions

• pharmacological activity is very similar to LSD

Preparation of Peytote

• entire plant is psychoactive

• only above ground portion is edible

• can be eaten green or made into tea

• dried then eaten

• dried mescal buttons remain psychoactive indefinitely

Nutmeg

Myristica fragrans

• contains catecholamine hallucinogen myristicin

• powdered nutmeg was used as a hallucinogen in Old World

• aphrodisiac powers (Yemen)

• Mace (flesh covering seed) contains different active ingredients with similar effects

What is this compound

Myristicin

Fly agaric mushroom

Amanita muscaria

• amino acid targets

• Ibotenic acid, muscimol, muscarine (no psychoactive)

Historical uses of Fly agaric

• oldest and most widely used hallucinogenic drug

• 3500 years ago, the Soma cult of the Indus ValleY

Compounds of Amanita muscaria

• muscimol

• Muscarine

• Ibotenic acid

Ibotenic acid

• Ibotenic acid and muscimol produce similar behavioural states despite very different mechanism of action

• Activates glutamate receptors

• Glutamate is an endogenous excitatory neurotransmitter → binds to receptor that act as ion channels

Muscimol

• the most active compound in fly agaric

• GABA receptor agonist

Muscimol effects

• produces state of confusion, disorientation, sensory disturbances

• Fatigue, sedation, sleep

• Cognitive ability dimished

Effects of ingesting fly agaric

• ingestion for one to four mushrooms for effects

• Derangement of senses then manic behaviour

• Delirium and altered perceptions of size

• General inhibition of motor function

Gauss

• German doctor

• Uses drug to allow for “twilight sleep” for women during childbirth

Modern scopolamine use

• Post-operative Nausea

• Motion Sickness

• GI Spasms

• To aid in GI radiology and endoscopy – Irritable Bowel Syndrome

• Eye Inflammation

What kind of compound is scopolamine

Alkaloid

CNS effects of scopolamine

• delirium

• Mental confusion

• Loss of attention

• Drowsiness

• Loss of memory for recent events

• Death

Cordwood Tree

Duboisia myoporoides

• leaves have concentration of atropine

• Aborigines submerged branches of tree into eel populated pools

• Eels become lethargic and easy prey

Other species

• Hyoscyamous niger

• Atropa belladonna

Colchicine

Mode of action

• inhibits mitosis

• Disrupts micro tubes

Uses in modern medicine

• treat gout

• Derivatives used to treat cancer

Side effects

• narrow therapeutic index results in overdose

• Damage bone marrow

May apple

Podophyllum peltatum

• root extract, long history among indigenous peoples of American Northeast in treating skin cancers

Active ingredients

• Aliphatic alkaloids, podophyllins

• Podophyllotoxin and a-peltatin

Podophyllotoxin

Mode of action

• stops replication cellular & viral DNA replication

• Destabilizes microtubules to prevent cell division

Uses in modern medicine

• treat HPV

• Derivatives used to treat cancer

Side effects

• Embryotoxic

Autumn Crocus

Colchicum autumnale

• extracts inhibit cell division

• Colchicine alkaloid

• Disrupts spindle formation during mitosis

Red clover

Trifolium pratense

• salve made from the flowers

• Isoflavone genistein as anti-oxidant

• Effective against breast cancer

Taxine

• From Taxus

• Toxic alkaloid assemblage composed of more than seven alkaloids

Taxol

• market name for paclitaxel

• Alkaloid

• Active anti-cancer agent in pacific yew

Taxol mode of action

• blocks cell replication

• M phase of cell cycle (mitosis and cytokinesis)

• Late anaphase/telophase the spindle structure is lost

• Paclitaxel binds to microtubles and prevents disassembly

• Cannot complete division

Madagascar periwinkle

Catharanthus roseus

• herbal medicine → wasp stings, stop bleeding, eyewash, diabetes treatment

• Plant extracts inhibit leukaemia in mice

• Active anti-cancer agents

Bloodroot

Sanguinaria canadensis

• Indigenous peoples used red sap used to treat breast cancer

• Today, used in conjunction with surgery to treat skin cancer

Sanguinarine

• used in oral rinses and toothpastes

• Effective against oral plaque forming organisms

What is this compound

Sanguinarine

Anti-malarial drugs

Quinine and Artemisian

The Dark Ages

• 1500 years with little knowledge on cause or treatment

• spread of malaria in Europe and the New World

• Association with swamps and marshes led to believe that malaria was caused by malignant

  vapors (miasmas)

• Paludisme roughly translate “of the marshes”

Charles Louis Alphonse

• discovered malaria parasite (1880)

• Noticed parasites in the blood

Causes of malaria

• four species of protozoans from the genus Plasmodium cause different forms of disease

• Cerebral malaria results in death if untreated

• Initiated but bite of female Anopheles mosquito

Symptoms:

• reoccurring bouts of fevers, chills, and anemia

Result of merozoites released into bloodstream

• sporozoite form of parasite multiples in liver (merozoites are created)

• Merozoites invade red blood cells → multiple rapidly, deplete RBC

• RBC cell rupture occurs 48-72 hours after invasion → causes fever and chills

• Some species can remain dormant for years

Malaria cure

• late 16th century/early 17th century

• Indigenous people used mark of a mountain rain forest tree to treat fevers (Incas, Cinchona bark)

Quinine

• alkaloid

• Found in Peruvian tree bark

• Odourless white powder

• Interferes with merozoite action

• Prevents polymerization of heme into hemozoin resulting in toxicity to parasite

Synthetic anti-malarial drugs

• Chloroquine, malarone (atovaquone/proguanil), mefloquine

• Used to target different Plasmodium life cycle stages and strains

what is this compound

chloroquine

How does quinine work?

• degrade hemoglobin to acquire essential amino acids

• Digestion carried out in vacuole of the parasitic cell. During this process, the parasite release the toxic

  and soluble molecule heme.

• the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule

• preventing the formation of hemozoin

Wormwood

Artemisia annua

• quinine alternative

• fever reduction

• terpene compound called Artemisinin

• produced in trichomes

How is artemisian synthesized

farnesyl diphosphate (FDP) → sesquiterpene intermediate → artemisinic acid → dihydroartemisinic acid → artemisinin

Pathway intermediates of Artemisian

IPP, DMAPP and GPP

Absinthe

Artemisia absinthium

• mass produced at the Pernod distillery

• originally a cough medicine

• thought to infuse the drinker with creativity, intelligence and glamour

Plant mixture

• variety of plant extracts including fennel, sweet balm, hyssop, angelica, and anise

• most important plant is variety of wormwood

absinthism

• Associated with epileptic seizures, orgy behavior, sexual diseases, corrupted artists, criminals

• Mimics of absinthe sometimes contain grain alcohol and copper salts (for color)- possibly toxic

Thujone

• terpene

• responsible for absinthes effects

• increased creativity (good)

• absinthism (bad)

What does Thujone do?

• binds to and blocks GABAA receptors in brain neurons

• Release of chloride into postsynaptic neurons reduces synaptic activity

• Inhibition of normal GABA activity may lead to the seizures seen when under the influence of thujone

Steps in genetic engineering of Artemisian

Steps 1 and 2:

• increase amount of substrate available (FPP)

• modify expression of several genes responsible for FPP synthesis

Step 3:

• They isolated genes encoding enzymes responsible for oxidizing amorphadiene to artemisinic acid

Toxin

poisonous substance produced by cells or living organisms

Death of Cleopatra

experiments with different plant extracts on slaves

• Henbane and Belladonna work quickly, but are painful

• Strychnine works quickly, but leaves the face distorted

• Supposedly, she decides on Asp’s venom

History of Poisons

• Assyrians wrote of plant poisons over 3000 years ago

• Greeks attribute discovery of poisonous plants to Hecate

• Roman herbalists were often accomplices to murder (readily available)

• Arab cultures in 9th century perfect the art of poisoning

How to avoid being poisoned

• Avoid eating foods that smell or taste ‘wrong’

• Use special goblets → would explode if poison was placed in the drink

• Use special stones to neutralize poison → toadstones, bezoar stones

Antidotes and Cures

• most cures instruct victim to induce vomiting

• Theriaca ( Greek ‘theriakon’ meaning remedies for venomous bites')

• Nero poisons his stepbrother to gain the throne

Acetylcholinesterase

• quickly removes acetylcholine from synapse

• Physostigmine inhibits acetylcholinesterase, resulting in more acetylcholine in the synapse

Cardiac glycoside arrow poisons

• Acokanthera, Parquetina, and Strophanthus genera

• Produce compounds like Ouabain and Strophanthidin

• cardiac glycosides are mixed with a binding agent

Ouabain

• cardiac glycosides

• used on arrows by hunters in Africa

Mechanism of action

• Inhibits the sodium/potassium ATPase that maintains ion gradients in heart muscle cells

Toxic Phenolics

• Lignans → Podophyllotoxin

• Coumarins → Aflatoxins, Methoxypsoralen

• Tannis

• Other phenolics → Urushiol

Aflatoxin

Aspergillus sp.

• fungus

• contaminate corn, cereals, sorghum, peanuts

• carcinogenic to humans and animals

• • Toxin intercalates and alkylates DNA, inducing mutation

Mithridates Eupator

• paranoid of being poisoned

• Took small doses of poison to make himself immune

• Tried to poison himself but was too tolerant

• Slave stabbed him to death

Cyclopamine

Veratrum californicum

• alkaloid

• Teratogen

• Inhibits normal protein patterning in developing organisms

• Named after mythical cyclops spoken of in Homer’s Odyssey

Aconitine or Aconite

Aconitum napellus

• Monkshood, friar’s cap, auld wife’s huid

Mechanism

• reduces ion selectivity if sodium channels

• Increase uptake of sodium

• Produces cardiac arrhythmias

Traditional medicine

It is the sum total of the knowledge, skill, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness.

Ethnobotany

• indigenously-informed plant identification, foraging, and cultivation in use as food, medicine and shelter