psychedelics Flashcards
What are psychedelics
Psychedelics are a class of psychoactive substances that can alter perception and mood and affect numerous cognitive processes – term coined by Humphry Osmond in 1957
Induce experiences quantitatively different from ordinary consciousness
History of psychedelics (entheogens)
mescaline can be mixed with water to make a drink with hallucinogenic properties
Ayahuasca contains DMT giving it’s hallucingoenic properties
AYAHUASCA- DMT
PEYOTE CACTUS- MESCALINE
MAGIC MUSHROOMS- PSILOCYBIN
What is LSD
Lysergic acid diethylamide (LSD) is a synthetic drug used during the 1950-60s as an experimental drug in psychiatric research for producing “experimental psychosis”
From the mid 1960s, it became a recreational drug of abuse with widespread use that continues today
Usually taken in tablet form, liquid form or on small squares of absorbent paper
What are magic mushrooms
Psilocybin first isolated by Albert Hofmann in 1957 from the Central American mushroomPsilocybe mexicana
It has since been found in more than 100 mushroom species with varying potency
Psilocybin (prodrug) is converted into pharmacologically active psilocin in the body
Widespread use as a recreational drug of abuse
structures of different psychedelics
catecholamines, indoleamines and lysergamides
catecholamines: benzene ring, 2 hydroxyl groups
dopamine is a naturally occuring catecholamine, with benzene ring and side amine group
mescaline is the psychodelic version
indoleamines have an indole group- bicyclic ring structure with benzene ring and pyrol ring
serotonin is naturall indoleamine- indole group- side chain amine
psychedlic: DNT, psylosin (magic mushroms)
lysergic acid amides include LSD and its analogues
can be considered pseudo indoleamine
Recap of dopaminergic signalling?
D1-D5 D 1 and 5 are pre synaptic Gs proteins 2,3,4 pre and post G11 proteins dopamine is terminated by MAO reuptake by DAT
Dopamine metabolised by monoamine oxidase (MAO)
Dopamine recaptured into nerve endings by a selective dopamine active transporter
There are four major dopaminergic pathways in the brain – the tuberohypophyseal, nigrostriatal, mesocortical and mesolimbic pathways.
psychodelics mainly affect meoscortical and mesolimbic pathways
mesocortical- vta to cortex. dopaminergic neurones from vta to cortex associated w feelings of cognitive control, motivation and emotion
mesolimbic- vta to Na.
dopaminergic neurones from vta to na associated w feelings of reward
Recap of serotonergic signalling
serotonin works in cns and pns
metabolism terminated by MAO
haluasca mixed contains alkaloid called harmine which is reverse monoamine oxidase inhibitor
serotonin reuptake into neurones via SERT
The raphe nuclei is a collection of nuclei located in the brainstem – serotonergic projections to vast parts of the central nervous system (CNS).
raphe nuclei are nuclei in brainstem
on both sides of midline
projecting to CNS
innervate cerebral cortex, amygdala, hypothalamus, amygdala, cerebellum, spinal cord
raphe nuclei fire rapidly during wakefulness
therefore these sertonergic projections regulate sleep and wakefulness
Receptor Transduction
1A, 1B, 1D, 1E, 1F Gi/o to inhibit adenylyl cyclase
2A, 2B, 2C Gq to stimulate IP3 and DAG formation
3 Ligand gated ion channel
4 Gs to stimulate adenylyl cyclase
5A, 5B, 6, 7 Gs to stimulate adenylyl cyclase by 6 & 7; 5 not established
How can psychedelics have dopaminergic and serotonergic effects
Users of psychedelic substances often report experiences that fall into one of these two categories
DA-like psychedelics: Energetic Empathogenic Cognitive control Motivation Emotion
5-HT-like psychedelics: Hallucinogenic Disorientating Somatically heavy Mood Sleep Sensation Memory processing Cognition (Digestive functions)
psychodelics can activate both directly and indirectly serotonin and dopamine subtypes
when someone takes psychodelic drug, huge increase in serotonergic and dopaminergic activity in the brain
dopamine and serotonin include mood, memory processing cogintiion, reward etc
use of psychodelics often leads to 2 category effects
dopamine- like psychedelics (catecholamines) such as catcholamines such as emescelin have dopamine like effects like energy and empathy
serotonin like psychedelics include indoleamines such as DMT and psylacibin mediate serotonin like effects like hallucinogenic effects, disorientation etc
What is the relationship between 5-HT2A binding and hallucinogenic potencies?
-HT2A binding affinity is a predictor for hallucinogenic potency
5-HT psychedelic drugs in order of 5-HT2A potency
5-HT2A associated with visual hallucinations
5-HT2C also associated with visual hallucinations
5-HT7 stimulates reward, correlate psychedelic action
Non-visual hallucinogens (audio)
Drug Names
A number of drugs tested for affinity at 5 HT receptors
4 is high affinity, 2 and under is not that much affinity
table shows to 5HT2A- indicator of hallucinogenic potency-particularly visual hallucinations
LSD has highest affinity,MDMA doesn’t
5HT2C is also associated w visual hallucinations- look at table very similar to 5HT2A and 5HT 7
blue box shows non visual hallucinogens like mescaline- low potency for the visual receptors but high for 5HT7 as that’s associated with non visual associations
this theory of affinity to receptor and sensations experienced link doesn’t hold true for all compounds
eg 6FDMT has high affinity for 5HT2A receptors but not responsible for mediating psychedelic effects
other factors such as pharmacokinetic profiles and coupling to neuronal signalling pathways
Give an example to go against this rule using LSD and lisuride
LSD and lisuride both have high affinity at the 5-HT2A receptor – however, LSD is hallucinogenic and lisuride is NOT hallucinogenic
LSD and anti-parkinsons drug lisuride
they both bind to 5HT2A on cortical pyramidal neurones with high affinity- LSD slightly higher affinity
affinity to 5HT2A receptor is predictive of visual hallucinogenic properties
so why is lisuride not psychedelic or hallucinogenic whilst LSD is
that means other than receptor affinity other factors must be important for mediating halucinogenic effects?
LSD and lisuride both bind at 5-HT2A receptors on the same cortical pyramidal neurons
It has been proposed that LSD stabilises the 5-HT2A receptor in an active conformation that couples to a signalling pathway responsible for its psychedelic effects
This signalling pathway involves coupling to heterotrimeric Gi/o proteins and Src (a tyrosine kinase)
specific mechanism of bidning differs
LSD stabilises 5HT2A recpetor in active conformation. coupled to distinct signalling pathways- GiO and SRC (tyrosine kinase proteins).
however lisuride does not stabilise 5HT2A receptor in active conformation so does not have these downstream signalling pathways- no psychedelic effect
How does molecular structure determine how long it takes a drug to be metabolised in the body
Molecular structure also determines how long it will take for a psychedelic drug to be metabolised in the body.
molecular structure of drug also impacts metabolic profile
ayahusasca developed by boiling 2 dif plans together
one of the parts- the amazonian vine contains alkaloid that’s a reversible MAO inhibitor- prevents the psychoactive substance DMT being broken down when it’s ingested
so it can assert psychoactive effects on body
LSD has complex structure
it has slower rate of metabolism, increasing time it’s present in the body for
Summary for psychedelic pharmacology
molecular structure- catecholamine (eg dopamine), indoleamine like (serotonine)
influences phsyiological effects
affinty to receptor eg 5HT2A can be predictive of HT2A potency, but as we saw w anti-parkinsons drug lisaride- not always the case
metabolic pathways- eg in LSD- can take drug longer to break down in body
designer drugs aim to increase psychedelic potency
Describe some physiological effects of psychedelics
Physiological effects associated with psychedelics depend on a range of factors – but ultimately – interfere with dopaminergic and serotonergic modulation.
Psychedelics can act as partial or full agonists at multiple receptors – not only 5-HT and DA receptors
Multiple receptor subtypes at pre- and post-synaptic localisations
Psychedelics can therefore act to excite at some, but inhibit at other, synaptic localisations
Psychedelic action can be described as modulatory signal interference…
psychedlics can bind to serotonin or dopamine receptors
can also bind to noradrenergic receptors
therefore able to interact w mulitple receptor subtypes in pre and post serotonin regions
act to excite some and inhibit others depending on which receptors are expressed at that synapse
How can psychedelics lead to extreme excitation
Psychedelic signal interference with 5-HT pathways promotes disinhibition, leading to extreme excitation.
if psychedlic drugs activates hippocampus (memory) and occiptital lobe (houses visual cortex)- can cause hallucinations
if this drug activates neural assemblies associated with self awareness eg frontal cortex- causes expanded consciosuness
Give an example to highlight the phsyiological effects of LSD- LSD vs placebo
LSD selectively expands global connectivity in the brain
Cortical areas showing increased global connectivity overlapped significantly with a map of 5-HT2A receptor densities
Compromises brain’s modular organisation and, simultaneously, the perceptual boundaries between the self and the environment
LSD increases global connectivity in brain
cortical areas shown activated by LSD overlapped with 5HT2A receptor map
compromises perceptual boundaries between self and environment
perceptual overload can make you see flickering of lights, light halos etc
