Psychedelics Flashcards
What are psychedelics? (2)
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
They are known to induce experiences… (4)
quantitatively different from ordinary consciousness
-meditation
-dreaming
-trance
-religious ecstasy
Psychedelics/“entheogens” have a long history of use in medicine and religion such as: (3)
Peyote cactus (North America)(mescaline)
Ayahuasca (DMT) (South America: boiling of both
Banisteriopsis caapi + Psychotria viridis
= drink
Lysergic acid diethylamide (LSD) (3)
- 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
Magic Mushrooms (4)
- 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
3 Psychedelic chemical structure classes (3)
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
recap of dopaminergic signalling (3)
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)
four major dopaminergic pathways in brain but what 2 are most important in psychedelics and what functions do they have? (4)
- mesocortical (VTA - projecting on pre-frontal cortex) = cognitive control, motivation + emotion
+ - mesolimbic (VTA to limbic (Nucleus accumbens) = reward
recap of serotoninergic signalling (5)
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)
So how are serotonergic neurones distributed in the brain?
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
When do Raphe nuclei cells fire most rapidly and what does that tell you about serotonin?
During wakefullness - when we are active
+ are mostly inactive when we’re asleep
= serotonergic projections used sleep reg.
What other effects does serotonin have in regards to psychedelics? (5)
(sleep)
Mood
Sensation
Memory processing
Cognition
(Digestive functions = GI disturbances + nausea side effect)
What category do users fall into after taking a psychedelic? (2)
DA-like psychedelics:
* Energetic
* Empathogenic
or
5-HT-like psychedelics:
* Hallucinogenic
* Disorientating
* Somatically heavy
How do psychedelics mediate their effects?
by binding to endogenous neurotransmitter
receptors (e.g., DA and 5-HT receptors).
Define Affinity
propensity to bind to a receptor
Define Efficacy
effectiveness at activating a receptor
What is the relationship b/w 5-HT2A binding and hallucinogenic potencies? (2)
Glennon et al
found as affinity increases = greater hallo effect
= 5-HT2A binding affinity is a predictor for hallucinogenic potency
Ray 2010 study - receptor affinity + hallogenicity of psyche’s (6)
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…
receptor affinity limited proof: LSD vs Lisuride (anti-parkinson’s drug) signalling cascade (5)
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)
Molecular structure + metabolism -e.g. Ayahuasca (3)
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
Molecular structure + metabolism -e.g. LSD (20
complex structures affect rate of metab. e.g. LSD
slower rate of metab = prolong effects of drug + increase duration of psyche trip
What do designer drugs do?
Many “designer drugs” have these complex tails to increase the duration
of the trip
Psychedelic pharmacology summary (3 factors) (6)
- 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
Physiological effects of psychedelics- ag or antag? (3)
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
What can psyche action be described as?
Psychedelic action can be described as
modulatory signal interference (hat is usually preceded over by DA/SER) = mediated drugs’ physiological effects
Potential effects due to interference (3)
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
pharm + phys effects - placebo vs LSD (effects) (4)
- 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
Layer 5 (V) cells in cortex background (6)
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
Layer 5 strict timing (4)
- 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
Perceptual overload symptoms + explained (5)
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
Psychedelic physiology summary (3)
- 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
