Psychedelics

Question 1

What are psychedelics? (2)

Answer 1

a class of psychoactive substances that can alter perception and mood and affect numerous cognitive processes – term coined by Humphry Osmond in 1957

Greek:
ψυχη psyche, ‘soul, mind’
δηλειν delein, ‘to manifest

Question 2

They are known to induce experiences… (4)

Answer 2

quantitatively different from ordinary consciousness

-meditation
-dreaming
-trance
-religious ecstasy

Question 3

Psychedelics/“entheogens” have a long history of use in medicine and religion such as: (3)

Answer 3

Peyote cactus (North America)(mescaline)

Ayahuasca (DMT) (South America: boiling of both
Banisteriopsis caapi + Psychotria viridis
= drink

Question 4

Lysergic acid diethylamide (LSD) (3)

Answer 4

• 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 DoA with widespread use that continues today
• Usually taken in tablet form, liquid form or on small squares of absorbent paper

Question 5

Magic Mushrooms (4)

Answer 5

• Psilocybin first isolated by Albert Hofmann in 1957 from the Central American mushroom Psilocybe 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 DoA Magic mushrooms

Question 6

3 Psychedelic chemical structure classes (3)

Answer 6

Catecholamines: Catehol ring structure + Dopamine (e.g.’s Mescaline + 2-CB)

Indoleamines: indole group + serotonin (e.g.’s DMT + Psilocybin + psilocin)

Lysergamides: LSD + its analogues = more complex structure than the other 2
but can be considered pseudo-indoleamine due to structure

Question 7

recap of dopaminergic signalling (3)

Answer 7

works by activating GPCR’s (D1-D5) D1 + 5 = pre-synaptic, but D2,3,4 = pre +post synaptic

DA action is determined metabolism by MAO

DA re-uptaken by DAT (transporter)

Question 8

four major dopaminergic pathways in brain but what 2 are most important in psychedelics and what functions do they have? (4)

Answer 8

• mesocortical (VTA - projecting on pre-frontal cortex) = cognitive control, motivation + emotion
  +
• mesolimbic (VTA to limbic (Nucleus accumbens) = reward

Question 9

recap of serotoninergic signalling (5)

Answer 9

Neurotrans in PNS + CNS

works by activating GPCR’s (5HT1-5HT7): 5HT1 is a ligand gated ion channel not GPCR

(r: A, 1B, 1D, 1E, 1F = Gi/o to inhibit adenylyl cyclase

r: 2A, 2B, 2C = Gq to stimulate IP3 and DAG formation

r:3 = Ligand gated ion channel

r: 4 = Gs to stimulate adenylyl cyclase

r: 5A, 5B, 6, 7 = Gs to stimulate adenylyl cyclase by 6 & 7; 5 not
established)

Serotonin metabolised by MAO

MOAi (inhibitor found in the boiled brew) = prevents DMT breakdown when ingested = psychedelic effects

SE re-uptaken by SERT (transporter)

Question 10

So how are serotonergic neurones distributed in the brain?

Answer 10

important region = raphe nuclei - a collection of nuclei located in the brainstem (either side) - projecting onto CNS

e.g. hypo, hippo, cerebellum , thalamus + amyg, spinal cord

Question 11

When do Raphe nuclei cells fire most rapidly and what does that tell you about serotonin?

Answer 11

During wakefullness - when we are active

+ are mostly inactive when we’re asleep
= serotonergic projections used sleep reg.

Question 12

What other effects does serotonin have in regards to psychedelics? (5)

Answer 12

(sleep)

Mood
Sensation
Memory processing
Cognition
(Digestive functions = GI disturbances + nausea side effect)

Question 13

What category do users fall into after taking a psychedelic? (2)

Answer 13

DA-like psychedelics:
* Energetic
* Empathogenic

or

5-HT-like psychedelics:
* Hallucinogenic
* Disorientating
* Somatically heavy

Question 14

How do psychedelics mediate their effects?

Answer 14

by binding to endogenous neurotransmitter
receptors (e.g., DA and 5-HT receptors).

Question 15

Define Affinity

Answer 15

propensity to bind to a receptor

Question 16

Define Efficacy

Answer 16

effectiveness at activating a receptor

Question 17

What is the relationship b/w 5-HT2A binding and hallucinogenic potencies? (2)

Answer 17

Glennon et al

found as affinity increases = greater hallo effect

= 5-HT2A binding affinity is a predictor for hallucinogenic potency

Question 18

Ray 2010 study - receptor affinity + hallogenicity of psyche’s (6)

Answer 18

Some drugs have high affinity at a number of 5-HT receptors but are NOT hallucinogenic

1) drugs rated for affinity at 5HTr subtypes + ranked (4= high, <2= imperceptible)

2) 5HT2a involved in visual hallucinations
= LSD highest affin (3.54)
= MDMA does not bind at all (0.00)

3) 5HT2C also associated
with visual hallucinations
= mirrors 5HT2A

4)5-HT7 stimulates reward, correlate psychedelic action = mirrors 5HT2A

5)Non-visual hallucinogens
(audio) - low affinity at 5HT2A but high affinity at 5HT1A

other factors are also important in mediating psychedelic effects (e.g., pharmacokinetic
profile, neuronal signalling pathway…

Question 19

receptor affinity limited proof: LSD vs Lisuride (anti-parkinson’s drug) signalling cascade (5)

Answer 19

LSD and lisuride both have high affinity at the 5-HT2A receptor

however, LSD is hallucinogenic + lisuride is NOT hallucinogenic

both MoA’s differ: mouse study
* proposed that LSD
stabilises the 5-HT2A receptor in an active conformation that
couples to a signalling pathway
* This signalling pathway involves coupling to heterotrimeric Gi/o
proteins and Src (tyrosine kinase)
* Lisuride does not stabilise 5HT2A receptor in an active confirmation =
lack of coupling to distinct signalling pathways responsible for LSD’s psyche effects

(used 5HT2A k/o mice to show no effects when using LSD - restored = see effects again)

Question 20

Molecular structure + metabolism -e.g. Ayahuasca (3)

Answer 20

Also determines how long it will take for a psychedelic drug to be
metabolised in the body

1) prepared by boiling of 2 plants = psychoactive brew drunk by users

2)MOAi (inhibitor found in the boiled brew) = prevents DMT breakdown when ingested = psychedelic effects

Question 21

Molecular structure + metabolism -e.g. LSD (20

Answer 21

complex structures affect rate of metab. e.g. LSD

slower rate of metab = prolong effects of drug + increase duration of psyche trip

Question 22

What do designer drugs do?

Answer 22

Many “designer drugs” have these complex tails to increase the duration
of the trip

Question 23

Psychedelic pharmacology summary (3 factors) (6)

Answer 23

• molecular structure: drugs categorised at catecholamine-like (DA) or indolamine-like (SER) = can influence effects of psych drug
• Receptor binding profile: affinity to binding to r (5HT2A) = can be predictor of hallo potency but not always
• Metabolic pathways: complex structures (lsd) = increases trip

Question 24

Physiological effects of psychedelics- ag or antag? (3)

Answer 24

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

Question 25

What can psyche action be described as?

Answer 25

Psychedelic action can be described as
modulatory signal interference (hat is usually preceded over by DA/SER) = mediated drugs’ physiological effects

Question 26

Potential effects due to interference (3)

Answer 26

Signal interference with 5-HT pathways promotes disinhibition, leading to
extreme excitation

if interfering w/ brain asso w/ memory (hippo) and vision (occipital lobe) = hallucinations

if interfering w/ brain asso w/fault and self-awareness (pre-frontal cortex) = expanded feeling of consciousness

Question 27

pharm + phys effects - placebo vs LSD (effects) (4)

Answer 27

• LSD selectively expands global connectivity in the brain
• MRI scans: Cortical areas showing increased global connectivity overlapped significantly with a map of 5-HT2A receptor densities
• the intra-venous LSD compromised brain’s modular organisation and, simultaneously, compromised
  the perceptual boundaries between
  the self and the environment
  = can be manifested as seeing subtle flickering of lights/ geometric grids/ light halos/ loss of depth perception

Question 28

Layer 5 (V) cells in cortex background (6)

Answer 28

most Psychedelics = agonists or partial agonists of 5HT2A

6 layers in cortex:
1= outermost
6 = innermost

psychedelics mostly project onto layer 5 - projects down to thalamus (relays motor+sensory signals to other layers of cortex) + laterally within layer (5)

• Highest density of 5-HT2A expressed on L5
  dendrites
• Thought to enhance top-down reconstruction and rendering of sensory inputs

= Real-time sensory feedback allows seamless representation of perception across the cortex

Question 29

Layer 5 strict timing (4)

Answer 29

• Precise synchrony and temporal fidelity in these circuits is key
• L5 neurons process incoming sensory inputs every 30-60msec

taking psychedlics = destablisation of these L5 circuits
= global multisensory frame aliasing, feedback synesthesia + eventual perceptual overload

Question 30

Perceptual overload symptoms + explained (5)

Answer 30

subtle flickering of lights
geometric grids
light halos
loss of depth perception

Sensory filling relies on precise temporal
aliasing - Psychedelics disrupt this temporal aliasing = producing optical illusions

Question 31

Psychedelic physiology summary (3)

Answer 31

• Psychedelics can act at many different receptor
  types at different localisations to induce a range of effects (excite/ inhibit)
• Temporally precise cortical projections are key to our perception (sensory and cognitive - layer V)
• Psychedelics cause signal interference and disrupt the processing of sensory and cognitive information = perception overload