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Neuropharmacology > Psychedelics > Flashcards

Psychedelics Flashcards

1
Q

When was psychedelic use first known?

A

> 2000 years ago in greece

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2
Q

What does psychotomimetics mean?

A

Produce a mental state resembling psychosis (most do not do this)

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3
Q

What does hallucinogens refer to?

A

Includes many compounds, not just psychedelics

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4
Q

What does the term psychedelics refer to?

A
  • 1957 Humphrey Osmond ‘molecules with mind-manifesting capabilities which provide useful or beneficial properties to the mind’
  • David Nicols ‘powerful psychoactive substanced that alter perception and mood and affect numerous cognitive processes’
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5
Q

What deos psychoplastogens refer to?

A
  • David Olson et al, includes psychedelics that ‘can re-grow atrophies neurons and heal the brain’
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6
Q

What led to the resurgence in research into psychedelics?

A
  • Led by lack of innovation in new drug treatments in psychiatry
  • Evdience of therpeutic actions
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7
Q

What conditions has there been suggestion of efficacy of psychedelics?

A
  • Depression
  • Additction
  • PTSD
  • Also anxiety and OCD
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8
Q

Where have psychedelics been reclassified?

A
  • Australia, can be used alongside psychotherapies if one or two other therapies haven’t worked
  • Also in some states of the USA
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9
Q

What are the two chemical strucures of classical psychedelics?

A
  • Tryptamines
  • Phenethylamines
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10
Q

What are the tryptamines?

A
  • DMT (major component of iowasca)
  • Psillocin- ,ediates the effects and is the metabolic component of psilocybin
  • LSD- structure is similar to 5HT itself, unsuprising that they will bind to the 5HT receptors
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11
Q

What are the phenethylamines?

A
  • Mescaline
  • MDMA (psychedelic like properties)
  • Have similar structure to dopamine but primarily bind to 5HT receptors
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12
Q

What is the cyclohexone psychedelic-like properties drug?

A

Ketamine

Reason for the resurgence as is very successful with long lasting effects in treatment resistance and causes plasticity

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13
Q

What is the typical profile for LSD?

A

Lots of different receptors that it has verying different affinities for

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14
Q

Where is 5HT1A expressed?

A

In diffrent brain nuclei, medium and dorsal raphe are the main serotonergic outputs but also the hippocampus, lateral septum entorhinal cortex and the amygdala

Can see why we get activity in cognition and emotion

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15
Q

What receptor type is 5HT1A?

A

Gi/Go- decreases cAMP

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16
Q

Is 5HT1A pre or post synaptic?

A

Presynaptic and normally tend to have some control over how much 5HT is released yb the neurons

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17
Q

WHere is 5HT2A and 5HT2C expressed?

A

Deep layers of the cortex, PFC and visual but also the thalamus

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18
Q

What receptor type does 5HT2A and 2C use?

A

Gq/G11 si increases IP3 and DAG (more excitatory than 5HT1A)

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19
Q

Outline serotonin

A
  • Monoamine transmitter
  • Involved in sleep regulation, appetite, mood and social functioning
  • 14 receptors (family and subtypes)
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20
Q

What are psychedelics global effects in the brain?

A
  • Increased glutamate release from cortical projection neurons to VTA and dorsal raphe
  • Leads to increased prefrontal dopamine levels and to a lesser extent, mesolimbic dopamine levels
  • Leads to increased PF 5HT
  • Increased 5HT in the thalamus which is important because it takes the brake off the filtering system in the thalamus to the visual cortex (sensory overload and increased visual processing)
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21
Q

Outline psychedelic receptor circuits

A
  • Predominantly driven by 5HT2A and how potent they are at these receptors
  • Conentrate between the thalamus and the cortex, reciprocal and different regions but in particular PFC and visual cortex
  • Also other contributions feeding into the cortical thalamic pathway, subltle changes in different regions even through the major drives are cortical and thalamic
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22
Q

What is psychedelic primary mechanism of action in the cortex?

A
  • Many are full or partial agonists of 5HT2A on pyramidal neurons
  • Increase release of glutamate in layer 5 of the cortex (thalamuc and limbic regions too)
  • Glutamate acting via NMDA and AMPA receptors and a direct effect on 5HT2A receptros on pyramidal neurons in layer 5 increase BDNF neurons
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23
Q

What was a study shoung a PFC rat brain slice?

A
  • Showed connections between pyramidal neurons which have 5HT2A receptros on presynaptic nerve endings of the fibres from the dorsal raphe to the cortex
  • These further inhibit 5HT release or excitation of the presynaptic terminal
  • Also postsynaptic importance of 5HT2A and 2C on the cells bodies of pyramidal cells
  • 5HT2A shows biased agonism meaning it can recruit and bind different pathways within the neurons (not alqays Gq)
  • 5HT2A also on intracellular plasma membrane so some effects occur through this action
  • Also activity on tract B BDNF (binds to tract B receptor- allosterically modulating) so enhances the effect of BDNF when it is released from these neurons
  • Cameron et al 2023
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24
Q

What are two preclinical assays for measuring psychedelic effect?

A
  • Head twitch response
  • Discrimination model
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25
Q

Outline the head twitch response

A
  • Most translational behaviour assay in rodents
  • Rotational movement of head
  • Strong correlation between HTR in redents and hallucinogenic effect in humans
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26
Q

Why does the head twitch response occur in rodents?

A
  • Due to activation of 5HT2A receptors in the fronal cortex
  • But dose-response curves show biphasic effect, suggest not only receptor/mechanism involved
  • Erkiziz-Sanfamaria et al 2022
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27
Q

What happened to the head twitch response when applying an antagonist to the different 5HT receptors?

A
  • Don’t see an effect with 1A receptor, so there is unlikely to be a role of the receptor
  • 2C there is an attenuation of the receptors
  • 2A can almost completely block the head twitch response suggesting that 2A is the main receptor associated. Also KO mice for 2A do not get the psychedelic reponse
  • Erkiziz-Sanfamaria et al 2022
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28
Q

What is the drug discrimination model?

A
  • Rodents are trained to distinguish between a psychedelic and vehicle
  • Responses demonatrated through lever presses
  • On test day, no of responses to a test drug can show how much the test drug substitutes (partially to fully for the (training) psychedelic
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29
Q

What is the result of the drug discrimination model with different 5HT antagonists?

A
  • Discriminatory effect was lost/reduced with 5HT2A antagonist
  • Was reduced with 5HT2C antagonist
  • Limited reduction with 5HT1A
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30
Q

What effects are blocked by 5HT2AR antagonists?

A
  • Hallucinogenic effects
  • And are absent in 5HT2AR KO mice
  • DOI can still induce head twitch response in Gq KO mice
  • So may be induced byb distinct conformations of the 5HT2AR
  • However beta arrestin 2 required for psychedelic effects of LSD but not DOI
  • Suggests a location bias of 5HT2A and activation of disticnt heterodimeric complexes such as metabortopic glutamate, dopamine, cannabinoid and serotonin receptors
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31
Q

Outline the biased agonism of psychedelics

A
  • Psychedelics exhibit similar Gq and beta arrestin2 activity at 5HT2A
  • Beta arrestin-biased 5HT2A agonists lack psychedelic potential
  • 5HT2A-Gq signalling predics psychedelic potential
  • Non-psychedelis do not activate 5HT2A-Gq signalling efficacy threshold
  • My also play a role in tolerance and cross tolerance with psychedelics
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32
Q

How does the location bias of the 5HT2A receptors occur?

A
  • Many psychedelics are lipophillic
  • This means they have favourable physiochemical parameters to cross the BBB and cell membranes
  • There are large intracellular pools of 5HT2A receptors for example in the golgi and endoplasmic reticulum
  • These intracellular components are slightly acidic so protonation of psychedelics may occur and psychedelics therefore stay at produce sustained signalling through intracellulae compartment
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33
Q

What is the role of tract B activation?

A
  • Psychedelics are not direct tract B agonists, extracellular BDNF is necessary for their effects on tract B dimerisation and plasticity
  • They act allosterically by facilitating the effects of endogenous BDNF released in active synapses
  • Activity- dependent release of BDNF in stimulated synapses helps to selectively stabalise
  • Active synapses at the expense of inactive ones
  • This promotes neuronal growth at the active synapses
34
Q

What are 3 ways psychedelics work?

A
  • Neuroplasticity
  • Functional connectivity
  • Psychedelic experience
35
Q

Outline neuroplasticity in how psychedelics work

A
  • Neuritogenesis, spinogenesis and synaptogenesis
  • Tract B, mTOR, 5HT2A signalling pathway modulation, related to BDNF upregulation
36
Q

Outline how functional connectivity in psychedelic functioning works

A
  • Increase entropy (disorder)
  • Disrupt unhealthy patterns of thought
  • Provide opportunity for new connections
37
Q

Outline psychedelic experience in how psychedelics work

A
  • Intensity correlates with positive therapeutic outcome
  • Suggestibility, wonder, ineffability, boundlessness, noetic sense
38
Q

Why is neuroplasticity of psychedelics important in a therapeutic setting?

A
  • Depression and anxiety associated with atrophy of neurones in the PFC (retraction of neurites, loss of dendritic spines, loss of synapses)
  • Traditional antidepressants can cause increases in BDNF (part of the mechanism may be through increased neuroplasticity
  • Ketamine causes increases in BDNF, neuroplasticity with quick onset and longer duration of action through to be associated with these effects
39
Q

How have serotonergic psychedelics shown promise in a clinical setting?

A
  • Demonstrated quick onset and longer duration of action in depression and anxiety even after a single dose
  • In animal models such as the forced swim test and fear extinction learning
  • Also in clinical studies such as in treatment resistant patients
40
Q

What is some in vitro evidence of neuroplasticity of psychedelics?

A
  • Increase dendritic sprouting/neurite length in LSD, DMT and DOI
  • But changes in different compnents aren’t always statistically significant
  • Not necessarily increases in BDNF transcript and protein levels but this may be due to the time frame
  • 5HT2A antagonist lose the effect of the psychedelic as if use tract b receptor antagonist
  • Selective mTOR inhibitor also blocks the psychedelic effect
  • Ly et al 2018
41
Q

Which 5HT receptor is inhibitory and which is excitatory?

A
  • 5HT2A is excitatory
  • 5HT1A is inhibitory
41
Q

Is 5HT response to psychedelics more excitatory or inhibitory?

A

Excitatory as the main mechanism is through 5HT2A

42
Q

What glutamate receptor is predominantly bound to as a result of the release of glutamate?

A
  • In layer 6 and 5 neurons
  • Binds to AMPA as there are more available
  • But has local actions at NMDA
43
Q

What does the signalling through AMPA in layer 5 neurons cause?

A
  • Increase in BDNF
  • This binds to tract b receptors
  • Psychedelics also act as a positive allosteric modulator here
  • Tract b causes signalling through mTORC1 causing an increase in plasticiy and expression of different glutamate subunits (change in AMPA at the cell membrane)
  • Kadriu et al 2021
44
Q

How can you measure for functional connectivity and the binding to 5HT2A?

A
  • Use ligands specific to the receptors
  • Can be a labelled pscyhedelic or the psychedelic displacing a specific radioligand
  • We can then map the density of the receptors and where they are acting
  • Highest levels are in the frontal cortex and temporal (visual)
  • Predominant effects are through cortical regions
45
Q

What are the three levels to how functional connectivity changes?

A
  • Increased single neuron excitability
  • Entropic brain activity
  • Global brain connectivity
46
Q

Outline the increased single neuron excitability in functional connectivity

A
  • Neuronal level (layer 5 pyramidal glutamate)
  • Greater activation means increased ability to fire and how rapid the firing is

-Get more action potentials and firing of the layer 5 neurons

  • These neurons are responsible for intercortcal connections
  • Control the top level of management processing within the cortex
  • Nutt et al 2020
47
Q

Outline entropic brain activity in functional connections

A
  • The amount of energy associated
  • Ususally have low entropy occuring and organisations status in the brain
  • Brain behaves in certain patterns and limitations (rhythmic activity) between neurons and different brain rgoins
  • When take psychedelics, go from low entropy to high entropy, change the status of the brain to a more disorganised state
  • Nutt et al 2020
48
Q

Outline global brai connectivity in functional connections

A
  • Higher energy status and more disorganisation
  • Brain regions which do not normally connect now can
  • Increases the scope of which regions are talking and what the brain can do
  • Nutt et al 2020
49
Q

How can real time binding and functional changing of psychedelics be measured?

A

Imaging techniques such as

  • PET
  • fMRI
50
Q

What have imaging studies revealed about binding and functional changes that psychedelics cause?

A
  • High doses of psychedelics lead to high 5HT2A receptor occupancy
  • Intensity of effect correlates with dose and occupancy
  • Resting-state imaging allows general overview of the brain
51
Q

What are the principles of resting-state fMRI?

A
  • fMRI measures changes in blood flow
  • Resting-state fMRI looks at changes when a person is doing nothing over a period of time
  • Connected brain regions that show shanges in blood flow at similar times are likely to be connected
  • This allows us to look at functionally connected brain regions and how these change with psychedelics
52
Q

What are some certain innate behaviours which cause functionality at rest?

A
  • Attention/salience
  • Vision
  • Hearing
  • Sensorimotor processing
  • Executive control
53
Q

When at rest, what is the activity across a network called?

A

The default-mode network

This contrbutes to the brains ‘ordinary patterns and structures’

54
Q

What does the deault mode network (DMN) consist of?

A
  • High level cognitive areas such as the medial prefrontal cortex, posterior cingulate cortex and the inferior parietal cortex.
  • Not the only regions involved but are defined as the most important.
55
Q

What type of network is the DMN and what does it mean?

A
  • Task negative network
  • Regions show strongly correlated activity at rest
  • Regions are deactivated during cognitive goal-directed tasks
56
Q

What does entropy mean?

A

In relation to consciousness and neurodynamics, it can be defined as ‘a quantitative index of a dynamic system’s randomness or disorder’

High entropy means high disorder

57
Q

How can neuroimaging show entropy?

A

Can reveal certain functional connections that can be associated with primary states of consciousness and normal modern day waking consciousness

58
Q

How do psychedelics effect the DMN and entropy?

A
  • High levels of activity at rest in the DMN
  • When give psychedelic (psilocybin) get changes to low levels of activity
  • So the psychedelic is mimicking what is happening in the brain when we go into goal-mediated behaviours
  • Disrupts the connectivity of the DMN in a resting state, allowing the brain to function in a different way
  • Carhart-Harris et al 2014
59
Q

How do psychedelics change patterns and neurons rhythmic activity?

A
  • Functional connectivity is ordered when neurons are oscillating at a particular frequency in sync
  • Different frequency windows are involved such as alpha, beta, gamma, delta and theta
  • Different psychedelics have different effects on oscillatory power at different frequencies
  • Psychedelics generally decrease power and frequency in different frequency bands interfereing with top down processing in the cortex
60
Q

What mental health disorders are characterised with rigid thinking?

A
  • Depression
  • Anxiety
  • Addiction
  • OCD
  • Eating disorders
  • PTSD
61
Q

What does rigid thinking mean in terms of mental health disorders?

A
  • Functional activity is very ordered and difficult to break the pattern
  • The brain may be wired differently and stuck behaving in this particular way
62
Q

Why aren’t traditional drugs as effective as psychedelic potential?

A
  • Do not help reorganise disordered and break rigid thinking so much
  • Explains why they don’t work for everybody
  • Psychedelics can take it further and break the wiring causin better and longer lasting reorganisation of thinking
63
Q

What is the psychedelic network activity ‘shake up’?

A
  • Networks usually strongly connected becomes less connected
  • Networks only loosely connected become more connected
  • With psychotherapy alongside, the brain can become less constricted than usual and new patterns, thinking and ultimately behaviours become altered
  • Allows bottom up processing to occur and a re-education of the cortex
64
Q

What is REBUS (relaxed belief under psychedelics)?

A
  • Premise is connections in the DMN become weakened and can change the brains reactions to different sensory inputs
  • Based on theories of Carhart-Harris
65
Q

What are some issues with the REBUS hypothesis?

A
  • DMN is not the only network involved- can see changes in connectivity and differences in the brain workings between different people, psychedelics and whether we have a mental health disorder
  • Entropy is difficult to measure directly and few studies have been carried out
  • predictions are vague and difficualt to test properly
66
Q

What is the thalamic gating model?

A
  • To do with functional connectivity between the cortex and thalamus
  • The thalamus filters and processes sensory information going to the cortex (mainly the reticular nucleus)
  • Neurons from cortex project onto 5HT1A and 2A receptors on the gabaergic neurons
  • Stops the gabaergic neurons and unfiltered information enters the cortex (PFC and visual primarily)
  • Explains the extreme visual hallucinations and why this can be dose dependent and differences in effects between full and partial agonists
67
Q

How do psychedelics act in the thalamic gating model?

A
  • Interference with the filtering so more information enters the cortex
  • Hyperpolarisation of TRN neurons
  • Reduces the normal oscillatory activity required fro proper gating of sensory inputs
68
Q

What is the mystical experience?

A

The hallucinogenic or perception altering experience is linked with therapeutic potential

The higher dose, the greater the mystical experience

69
Q

How does therapy incorporate the mystical experience?

A
  • Involves a number of high-dose psychedelic dosing sessions
  • Occurs with before, during and after psychological sessions
  • Aim is to facilitate a profound, potantially transformative psychological experience
70
Q

How is the mystical experience measured?

A
  • Via questionnaires
  • MEQ (mystical experience questionnaire) Pahnke and Richards 1966
  • M scale Hood Jr, 1975
  • ASC (altered sates of consciousness questionnaire_ Dittrich 1998
71
Q

How was neuroplastic effects and changing in mood tested?

A
  • Using non-hallucinogenic 5HT2A receptor agonist
  • Tabernanthalog
72
Q

How have psychedelics been used for addiction?

A
  • Studies into alcohol dependence and LSD go back to the 1970s
  • Conflicting effects seen; lack of rigorous clinical research
  • Links made with mystical experiences amd psilocybin helping to treat addiction
73
Q

What is Ibogaine?

A
  • Attenuated withdrawal and craving, resulting in reduced drug-seeking behaviour
  • Abstinence from alcohol and stimulants has also been reported for a median of 5.4 months following a single ibogaine treatment, and 8.4 months after multiple treatments
74
Q

What is the study into alcohol dependence and psilocybin treatments?

A
  • Open-label study
  • 10 ppts meeting DSM5 for alcohol dependence
  • Two oral psylocybin sessions
  • Part of a 12 week motivational enhancement therapy program
  • Sustained decrease in amounts of drinking and heavy drinking in days (doesn’t stop completely)
  • Bogenschutz 2015
75
Q

Why is ibogaine not suitable for commercial development?

A
  • Over exploitation of plant
  • No scalable synthesis
  • Cardiovascular side effects
76
Q

Why is TGB (taberanthalog) a non-hallucinogenic analogue?

A

Doesn’t produce head twitch response

77
Q

What are TBG’s actions?

A
  • Potent 5HT2A receptor agonist
  • Devoid of opioid agonism
  • 5HT2B antagonism (underlie cardiovascular effects)
78
Q

What happens when give rodents TBG?

A
  • Intermittent exposure to alcohol
  • Allow initial binge and access to alcohol on day 1 and 3
  • After 4 weeks can see if they try to binge or reduce the consumption
  • Find with TNG, can get a change in the alcohol over the first few days but wears off after 5 days
  • Cameron et al 2021
79
Q

What are the issues with psychedelic research?

A
  • Small study sizes
  • Different methodologies such as collection and analysis of results and consciousness (resting or not)
  • Different doses and routes of administration
  • Controls (placebo can be different)
80
Q

Outline the study into psilocybin vs antihistimine in treating substance abuse disorder

A
  • Alcohol abuse
  • Criteria were met for alcohol dependence, days of consumption during the 12 week period prior, number of days heavy drinking, years of dependence and standard drinks per drinking day consumed
  • 94% guessed what treatment they were on
  • Psilocybin vs diphenhydramine
  • Was substantial decreases in both groups between screening and week 4
  • Ppts received 4 psychotherapy sessions and attempted to stop drinking in preparation for the first medical session
  • Both placebo and psilocybin decreased drinking days and the number of drinks per day
  • Overall effet over 5-36 weeks significant for psilocybin vs placebo
  • Bogenschutz et al 20022
81
Q

What are the subjective effecrs of psilocybin vs placebo?

A
  • MEQ scores
  • Session 1 psilocybin was 0.59 vs 0.10 for diphenhydramine
  • Session 2 psilocybin was 0.64 vs 0.11
  • These scores indivate high average intensity of experienes in the psilocybin group and low average intensity in the control group

Neuropharmacology (6 decks)

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