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
