Hallucinogens

What are psychoactive plants? what classes of drugs do they contain?

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

Includes: stimulants, hallucinogens, analgesic, sedatives, hypnotics and narcotics

What are the effects of hallucinogenic plants?

They all distort the perception of reality

Experience the dream world

Altered idea of time, space, sound, touch, smell taste and color

Affects cognition and mood

Can rarely cause confusion, memory loss, or disorientation

What is a hallucinogen?

any agent that causes alterations in perception, cognition and mood as it primarily psychobiological actions in the presence of otherwise clear sensorium

What is the entomology of psychedelic?

from Greek meaning “Mind expanding” or “Mind manifesting”

What is psychotomimetics?

‘Induced psychotic states’

Compared to schizophrenia; but schizophrenia has much different brain activity

What are the traditional uses of hallucinogenic plants?

Used worldwide by indigenous peoples for magic, medicinal and religious purposes

Gifts from the gods; or even the gods themselves

Mediate between the man and the supernatural; used by specific individuals or all members of a society

Who synthesized LSD? when?

Albert Hofmann in 1949

What is the difference in use of hallucinogens in the 60s vs 70s?

The 1960s were a psychedelic period; with widespread recreational uses of these drugs

While in the 1970s they were classified as as controlled substances

How many are estimated to use Hallucinogens in modern day America? (200&)

~14% (over the age of 12) at least once

~1-1.5% in the last month

What is a psychoplastogen? examples?

Small molecules that produce rapid and sustained structural and functional neural plasticity.

Considered therapeutics for depression, addiction and PTSD

Examples: Ketamine, MDMA, Scopolamine, LSD and Psilocin

What is the clinical uses of MDMA, Psilocybin, LSD and Ibogaine?

MDMA: In conjunction with psychotherapy for PTSD, Anxiety and Eating disorders

Psilocybin: For treatment of a variety of disorders including anxiety and depression.

LSD: For cluster headaches and anxiety

Ibogaine: For addiction

What are the three main categories of plant hallucinogenic compounds?

1. Monoamine (adrenergic) targets and pathways: Indole & Catechol hallucinogens

2. Amino acid targets and pathways

3. Cholinergic targets and pathways : Anticholinergic hallucinogens:

What are the characteristics of indole and catechol hallucinogens (monamines) ?

• Target serotonin related pathways

• Vivid sensory effects; changing colours and patterns

• Perception is altered while maintaining contact with the real world; User can remember their experience

• Low toxicity; user will not overdose

What is the ecology of ergot?

It is a parasitic fungi found on grains like rye and wheat during wet season. Spores are deposited by insects and grow hyphae into the ovary of grains to obtain nutrients.

What is ergotism?

Cattle and humans who eat infected grains get ergotism, symptoms include: gangrene, nervous spasms, psychotic delusions and convulsions

What is the early history of ergot?

In the Assyrian cuniform tablet from 600 BC

• Mentions a noxious pustule in the ear of grain

• But symptoms are not reported until 1676

Romans

• Refer to it as Ignis sacer “holy fire”; Burning sensations are reported in extremities; these symptoms are retributing for sins

→ There was a European epidemic in 944 A.D with ~ 40,000 deaths

• Associated with the Salem Witch Trials and the French Revolution

What are the chemicals in ergot?

A collective group of chemicals called ergoline;

Ergoline, Lysergic acid, Ergotamine and Ergine

What is the MOA of ergoline?

They show both antagonistic and agonist effects on serotonin, dopamine and adrenergic receptors

But how? → This is unknown

What are some of the modern medicine uses of ergot?

• Uterine contractions: used by european midwifes

• To reduce postpartum hemorrhage

• To treat migrates

• To reduce prolactin levels resulting from pituitary tumors

• To treat senility and Alzheimer's dementia

What is the precursor to Lysergic acid?

Tryptophan

What is the chemical name of LSD?

d-lysergic acid diethylamide

What does dosing of LSD look like?

Small doses intensify perception

Large doses cause hallucination (last 6-12 hours)

T/F LSD is not addictive?

True

Rapid and complete tolerance develops for behavioural effects after 4-7 days, and last for 3 days; also crosstolerance to other monoamine hallucinogens

Not addictive and doesn’t produce withdrawals

Massive overdose is required for lethal effects

What is the MOA of LSD?

Regulate serotonin pathways; binds multiple serotonin receptor subtypes (5HT receptors) with both agonist and antagonist effects

Tolerance is due to the downregulation of certain serotonin receptors

What neurotransmitter does this resemble?

Serotonin;

What are the effects of LSD?

Profound perceptual distortions and hallucinations

Distorted awareness of sensations and altered sense of self

Even mundane sensations and vivid and intense

This is variable from person to person

What is a ‘Bad trip’?

A panic episode brought on by dislike of drugs effects and fear that the experience will not end

→ Can result in flashbacks: hallucinogen persisting perception disorder

How are morning glories used for their lysergic acid content? historically vs a modern context?

Aztecs used these for divination purposes: priests eat seeds and interpret their visions to guide their flowers

Modern use by indigenous mexicans; they are ground into flour, soaked filtered and drunk

What are magic mushrooms called by aztecs?

Teonanacatl

Gods flesh

Who is Richard Evans Shultes?

The first botanist to record rituals and beliefs surrounding the magic mushroom

In 1941 he writes his Harvard doctoral thesis on this subject

What is the chemistry of Psilocybin (psilocin)?

• Structurally similar to serotonin

• Similar effects to lysergic acid and LSD (1% potency)

Who is Timothy Leary?

A Harvard professor who in the 1960s was the first to investigate the effects of eating magic mushrooms

What is a major precursor to psilocin?

L-tryptophan

What are the effects of Psilocybin?

30 minutes after ingestion = dizziness, weakness and twitching

30-60 minutes after ingestion = visual effects seen; colours, patterns and dreaminess, sense of euphoria develops

180 minutes after ingestion = normalcy returns

What does a ‘Bad Trip’ on Psilocybin look like?

Distortion of familiar objects

Distorted forms can appear threatening; people can appear as demons, facial distortions

What are the Catechol hallucinogens?

Mescaline & Myristicin

Similar effect in both groups although the compound structures differ

What does Peyote look like?

A small spineless cactus

Greenish top

Parsnip or carrot-like root

Endemic from southern Texas to central Mexico

Has >56 alkaloids

What is a catechole group?

A phenol with two OH groups attached to it

What active compound does peyote contain?

Mescaline

How long do the effects of mescaline last? symptoms?

6-10 hours

Dilation of pupils

Increase in pulse rate and blood pressure

Elevation of body temperature

What is the chemical structure of catechol hallucinogenic structures?

• Resemble catecholamine: norepinephrine, dopamine

• Effects mirror mechanisms of indole hallucinations via serotonin actions

• Pharmacological activity is similar to LSD (0.2% potency of LSD)

What are the historical uses of peyote?

Samples found in caves date to 8000 years ago

Used by the Aztecs; predating Spanish conquest; and they tried to eradicate its use; it was eaten during religious ceremonies by priests and their congregation

Used in Texas in 1760; as it spread through regional indigenous tribes by 1880

The Native American Church ; founded in 1918, groups practised ceremonial peyote use

How is peyote prepared?

• Entire plant is psychoactive; but only the above ground portion is edible

• The crown is sliced into small disks

• It can be eaten green or made into tea for drinking. 

• It is dried then eaten; Dried mescal button remains psychoactive indefinitely 

How is nutmeg used medicinally?

Used as a hallucinogen in Old world

In Asia it is often added to tobacco and chewed of snuffed

Aphrodisiac powers in Yemen

What is mace?

The fleshy covering around the nutmeg seed

Contains a different active ingredient with similar effects

Different flavours

What is the active compound in nutmeg? what are the effects?

Myristicin

Hallucinogen effect

• Similar to peyote; both in visual and imagined effects; colour kaleidoscopes, trance, out of body experience and flying

How is nutmeg prepared as a hallucinogen?

• Mix 1-3 tbs in water; serve hot

• The toxic compounds can result in hangover

What is the amino acid hallucinogen?

Amanita species = Ibotenic acid, Muscimol (most active)

What is the ecology of Amanita?

Amanita Species

50-60 species of Amanita

Widespread in the temperate regions of the northern hemisphere (NA and Asia)

Grows well under fir and birch trees; common on damp autumn days

What is the historic use of Amanita species worldwide?

-May be the oldest and most widely used hallucinogenic drug

India:

• Around 3500 years ago it was used by the Soma cults of the Indus Valley; Soma is a hallucinogenic plant thought to be god, it is mentioned 120 times in the Rig Veda

Northeastern Asia and Siberia:

• Observation of intoxicated reindeer

• A Swedish prisoner in Siberia in 1730 reported its use by his captors (used by shamans)

North America:

• Utilized by indigenous Ojibwa in Michigan

What is the MOA of ibotenic acid?

Activates glutamate receptors

(Glutamate is an endogenous excitatory neurotransmitter which binds to receptors that act as ion channels or that are G-protein coupled.)

Ion channels release Na+ or Ca2+ into the post-synaptic neurons leading to an excitatory response

what is the MOA of muscimol?

GABA receptor agonist

GABA is derived from glutamate but is an inhibitory neurotransmitter.

Muscimol activates GABA receptors that are chloride channels

What are the symptoms of muscimol?

• Produces a state of confusion, disorientation and sensory disturbances

• Fatigue, sedation and sleep

• Cognitive ability is diminished

What is the importance of muscarine?

• In 1869 Schmiedeberg showed that musarine could elicit excitation of the vagus nerve in frogs

• This observation stimulated a search for endogenous neurotransmitter substances with this effect

• This lead to the discovery of acetylcholine and its action on endogenous receptors

What are the effects of Fly agaric?

• Ingestion of 1-4 mushrooms for effects

• Onset of action is 15 minutes - 1 hour

Effects

• Derangement of senses, then manic behaviour

• Delirium and altered perception of size

• Desire for exaggerated physical activity

• Visual and acoustic hallucinations

• General inhibition of motor function

• After 12 hours, deep sleep

What is the Anti-cholingeric hallucinogen?

Scopolamine from the Corkwood tree, Henbane and Poisonous nightshade

What is the historical medicinal use of Scopolamine?

• Used clinically by 1910 ; as a pre-anesthetic medication, motion sickness

• In WW1 it was used for American GIs to combat seasickness

• A German doctor; Gauss in the 20th century prescribes it for a ‘twilight sleep’ of women giving birth

• Used as a tranquilizer in alcohol and drug withdrawal treatment

• Can be used in combination with morphine as a ‘truth serum’

What are the modern medicinal uses of Scopolamine?

• Post operative Nausea

• Motion sickness

• GI spasms

• To aid in GI radiology and endoscopy

• IBS

• Eye inflammation

What is the MOA of scopolamine?

• Muscarinic receptor agonist

• Hallucinogenic at higher doses

Has variou CNS effects …

What are the CNS effects of scopolamine?

→ As dosage increases a behavioural pattern emerges

• Delirium

• Mental confusion

• Loss of attention

• Loss of short term memory

• Death

Hallucinations and out of body sensations occur at the time of drowsiness and memory loss

→ Physostigmine has been used as an antidote

What is the ecology of the corkwood tree?

• Native to Australia, Queensland and north and central New South Wales

• Leaves have concentrations of atropine and scopolamine

• Aborigines submerged the branches of the tree into eel populated pools, the eels then became lethargic and easy prey

• There is not enough of this plant to meet scopolamine demand

What is the demand for scopalamine?

→ 10x higher commercial demand for scopolamine than hyoscyamine and atropine combined

… But plants produce less scopolamine than other alkaloids

How do we meet demand for medicinal plant compounds?

• Cultivation

• Cell culturing approaches; callus and hairy root culture

• Genetic engineering approaches (must understand the biology of secondary metabolite application)

What does the biosynthesis of scopolamine look like?

Begins with ornithine

Derived from hygrine

What are 2 other plants used for their production of scopolamine? their drawbacks/ benefits?

1. Henbane

• High levels of H6H enzyme

• Active H6H gene; transcribed at high rate = >H6H RNA

• But it is difficult to grow … unsuitable for cultivation

2. Poisonous nightshade

• Hyoscyamine producer

• Lower amount of H6H enzyme

• But it is easy to grow … suitable for cultivation