PSY3451 Lecture 8 Notes: Psychedelics, Plasticity & Psychiatry

Introduction to Clinical Neuroscience: Brains, Drugs & Psychiatry (PSY3451)

• Lecture 8: Psychedelics, Plasticity & Psychiatry: Novel Therapeutics?
• Dr. Alexander Shaw

Module Overview

• The module covers a range of topics, including:
  • Brain anatomy, physiology, and neurobiology.
  • Pharmacology (dynamics and kinetics).
  • Brain imaging methods (structure vs. function).
  • Clinical trials and imaging in psychiatric disorders.
  • Psychedelics and their potential as novel therapeutics.
  • Theoretical neuroscience.
  • Clinical Neuro Journal Club.
  • Neurostimulation as a therapeutic tool.

Today's Session

• Part 1: Psychedelics, plasticity & psychiatry: novel therapeutics?
• Part 2: Group experiments with the MUSE EEG headband: data collection.
• Part 3: Coursework deadline this week! (summative)

Topics to Be Covered

• Neuronal or synaptic plasticity.
• Mechanisms of LTP (NMDA, Serotonin 5HT-2a/c, neurogenesis).
• Clinical relevance of LTP: psychiatric disorders.
• Measuring plasticity in humans using M/EEG.
• Introduction to psychedelics.
• Psychedelic pharmacology: classical vs non-classical.
• The Psychedelic Renaissance in psychiatry.
• Ketamine-assisted psychotherapy.
• Psychedelics & plasticity: the route to novel and personalized treatments that actually work?
• Current work here in Exeter and elsewhere.

What is Neuronal Plasticity?

• Plasticity is the ability to be modulated.

Defining Neuroplasticity

• Synaptic plasticity: change in synaptic efficiency.
• Effects can be short or long term (focus on long term).
• 'Rewiring' can strengthen (long-term potentiation) or weaken (long-term depression) synaptic transmission.
• Mechanisms:
  • Synapse formation or retraction.
  • Spinogenesis.
  • Synaptogenesis (late synaptic plasticity).
  • Axonal sprouting.
  • Axon regeneration.
  • Dendrite growth and formation.
  • Neurogenesis.

Neuroplasticity Levels

• Molecular level:
  • Molecular changes.
  • Signaling pathways.
  • Gene transcription.
  • Protein synthesis.
• Cellular level:
  • Neurogenesis.
  • Dendritogenesis.
  • Synaptogenesis.
  • Proliferation, differentiation, survival, migration, maturation.
• Neuronal level:
  • Dendritic spine morphology and density.
  • LTP.
  • LTD.
• Structural vs Functional plasticity

Hebbian Plasticity

• "When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased."
• Cells that fire together, wire together.

Quick Neurobiology Reminder

• Key receptors:
  • AMPA: ionotropic, excitatory, responsive to sodium (Na), fast dynamics (~4 ms).
  • NMDA: ionotropic, excitatory, responsive to calcium. Blocked at rest by magnesium, activated when voltage reaches threshold to unblock magnesium. Slow dynamics (~100+ ms). Often co-located with AMPA.
  • GABA-A: ionotropic, inhibitory, fast dynamics (~5 ms).
  • GABA-B: metabotropic, inhibitory, very slow (~300 ms).
  • Serotonin: 7 types (one ionotropic (5HT3), rest metabotropic (5HT1, 2, 4, 5, 6, 7)). Can be both excitatory and inhibitory (neuromodulator), largely inhibitory effects.

How Do Synapses Change Their Strength?

• Simple synaptic process:
  • (presynaptic) neuron fires.
  • (presynaptic) neurotransmitter release.
  • binding of neurotransmitter to postsynaptic receptors.
  • opening of ion channels in postsynaptic neuron.
• Synaptic plasticity can change:
  • Amount of transmitter released.
  • Number of postsynaptic receptors available.

What Use Is Plasticity?

• Plasticity is thought to be the main process by which one can:
  • Learn new skills.
  • Establish new memories.
  • Response / adapt to injury.

Why Might Plasticity Be Useful in Understanding and Treating Psychiatric Disorder?

The Synaptic Process: NMDA Holds the Key

• Baseline Transmission: Current enters through AMPA receptors.
• Induction of LTP: Intense stimulation leads to expulsion of $Mg^{2+}$ ions from NMDA receptors and influx of both $Na^+$ (at AMPARs) and $Ca^{2+}$ (at NMDARs) ions.
• Increase in AMPA receptor numbers: AMPAR numbers are increased, which allows more current through leading to larger EPSP.
• Increase in AMPA receptor efficiency: AMPARs are chemically modified so that each receptor allows more current through, leading to larger EPSP.
• (EPSP is what generates EEG signal).

Measuring Plasticity In Humans Using M/EEG

Recall Evoked Responses (ERPs) from wk3 M/EEG

• Visual Evoked Potential (VEP) Test Example.
• Stimulus onset -> Evoked -> Average -> L
• The form of the VEP: N75, P100, N135
• Voltage across Time
• Amplitude of P100
• Latency of P100

What Effect Do You Think LTP Would Have On The Evoked Response?

• P200 potentiated
• Repetitive stimulation à increased synaptic efficacy à bigger response

A Real M/EEG Experiment For Measuring LTP

A Simple Task for Inducing & Measuring LTP in the Visual System

• 1 Hz (slow) presentation to get a stable baseline evoked response
• Faster 9 Hz presentation of fixed orientation – induce fast firing.
• Tetanus = stimulated to to create fast sequence of action potentials.
• Post tetanus, re-do 1 Hz presentation to establish short term synaptic changes from baseline response.
• Final 1 Hz presentation 35 – 40 minutes later to assess long term synaptic changes from baseline.

A Simple Task for Inducing & Measuring LTP in the Visual System

• Potentiation pf P2 component in late stage = LTP
• Closest EEG sensor to visual cortex.
• EEG signal extracted from visual cortex.

Step Further By Fitting A Synaptic Cortical Model To The EEG Data

• Model generated evoked potential after fitting to EEG
• Closest EEG sensor to visual cortex
• EEG signal extracted from visual cortex
• Model generated evoked potential after fitting to EEG

Modelling Means We Can Look At Receptor-Specific Connections Between Cell Populations - Induction Plasticity

• We set up 3 versions of the model:
  • 1. where the synaptic changes from baseline changed most at early post tetanus and normalised by late post-tetanus – adding support for shot-term potentiation (“non-linear”).
  • 2. where the synaptic changes from baseline linearly increased over early to late post tetanus – suggesting support for long- term potentiation (“linear”).
  • 3. A model combining both of the above.
• Model comparison provided most evidence for model 3 closely followed by model 2 - LTP.

Modelling Means We Can Look At Receptor-Specific Connections Between Cell Populations Induction Plasticity

• Parameters showed increased in AMPA mediated connectivity in key thalamo- cortical and cortico-cortical layers.

So Can We Use EEG-Measures of LTP to Understand Which Drugs Induce LTP and Harness That Effect Towards Treating People?

Mechanisms of LTP

• Serotonin / 5HT-2a/c
• Clinical relevance of LTP in psychiatric disorders?

Explored Whether Increased Serotonin By SSRI Enhanced LTP In Motor Cortex

• Placebo
• Baseline tDCS Motor potential (MEPs)
• 20 mg/d citalopram for 35 days
• 4 measurements of MEPs during treatment
• 2 measurements of MEPs while taking CIT
• 2 measurements of MEPs while taking CIT AND dose of dextromethorphan (150 mg) – NMDA receptor antagonist
• Remember NMDA receptor activation is key to LTP

Does Serotonin Boost LTP?

• In the placebo medication condition (square), tDCS induced a significant excitability enhancement for up to 90 min after stimulation.
• Citalopram (diamond) enhanced and prolonged these excitability enhancements until the next evening!

Does Serotonin Boost LTP?

• … but NMDA receptor block by dextromethorphan abolishes serotonin-dependent tDCS induced plasticity enhancements!
• No modulation with CIT+DEX

Does Serotonin Boost LTP? - Yes Summary –

• Increasing serotonin by SSRI increases LTP (in MEPs).
• Blocking NMDA receptors blocks this serotonin effect.
• Important questions –
  • If SSRIs increase LTP, and plasticity is good for treating psychiatric symptoms, why are they so ineffectual as treatments?
  • SSRIs are slow (need prolonged exposure) and not specific to a particular serotonin receptor… could there be a more specific (serotonin) receptor target for increasing plasticity?

Lots of Serotonin Receptor Types…

• 7 main Receptor Drug function / Usage Type of Plasticity
  • 5-HT1A Analgesics (agonists), Antidepressants, Anxiolytics (antagonists) adult neurogenesis, dendritic maturation, neuroprotection, astroglial interaction
  • 5-HT1B Migraines - triptans
  • 5-HT1D Migraines - triptans
  • 5-HT1E none
  • 5-HT1F none
  • 5-HT2A Psychedelics (agonists), AT psychotics (antagonists) synaptic plasticity, spine morphology, dendritic morphology
  • 5-HT2B Migraines (antagonists)
  • 5-HT2C Antidepressants (antagonists), Orexigenic – Clozapine (antagonists) synaptic plasticity
  • 5-HT3A Antidepressant, Antipsychotics neuronal migration, synaptic plasticity
  • 5-HT4 Gastroprokinetics spine morphology, synaptic plasticity, neurogenesis
  • 5-HT5A none
  • 5-HT5B none
  • 5-HT6 Antidepressants, Anxiolytics, Nootropic

Serotonin 5HT2A ?

• Could the 5HT2A receptor– the site where classical psychedelics act - be of importance for LTP induction?
• Been established for some time that 5HT2A is important for LTP…
  • 5-HT2A antagonism converted LTP to LTD in auditory cortex of mice – Lee et al 2018.
  • 5-HT2A antagonism blocked LTP induction in prefrontal cortex of mice - Zhao-hui Xu et al 2012
  • 5-HT2A agonism in neocortex increased LTP in mice – Vaidya et al 1997
    • … + more

Introduction to Psychedelics

• Psychedelic pharmacology: classical vs non-classical.
• The Psychedelic Renaissance in psychiatry.
• Ketamine-assisted psychotherapy.

Introduction to Psychedelics

• Psychedelics are a type of hallucinogenic drugs.
• Their primary effect is to trigger non-ordinary mental states – aka psychedelic experiences - "trips"
• and/or an apparent expansion of consciousness.
• Classical psychedelics = agonists of the 5HT-2A receptor
  • Psilocybin
  • LSD
  • Mescaline
  • 5-MeO-DMT
  • MDMA (*indirect agonist)
• Non-classical psychedelics = drugs with psychedelic-like properties but different receptor targets
  • Ketamine (NMDAR antagonist)
  • MDMA (*Dopamine RI)

The Psychedelic Renaissance in Psychiatry

Psychedelics as Medicines in Psychiatry

• Effective treatments are lacking in psychiatry.
• Researchers have been exploring the effects of psychedelic drugs as treatments for psychiatric disorder with remarkable results.

Psychedelics in Psychiatry: State of Play

Psychedelics in Psychiatry: State of Play

• Outstanding but important questions:
  1. Why are psychedelics so good at treating mental health conditions?
  2. Usually, we would look to the mechanism of action of the drug: … but we have multiple since
     • classical psychedelics agonise 5HT2A
     • non-classical psychedelics (ketamine) antagonise NMDA (or other systems)
     • …so, what do they have in common?

Enhancing Plasticity!

Psychedelics & Plasticity: Ketamine

• Sumner et al used the visual LTP EEG task during a clinical trial of ketamine for depression.
• In depressed people, the P2 component was significantly potentiated (increased LTP) by successful ketamine treatment but not placebo

How Do 5HT2A Agonism And NMDA Antagonism Both Lead To LTP?

• Normal LTP process: Increased stimulation à more $Na^+$ at AMPA receptors Enough $Na^+$ that NMDA $Mg^{2+}$ block dislodges, allowing $Ca^{2+}$ influx
• $Na^+$ = sodium, $Ca^{2+}$ = calcium, $Mg^{2+}$ = magnesium
• BDNF = brain-derived neurotrophic factor
• TrkB = tyrosine receptor kinase B
• BDNF along with increased glutamate induces LTP by binding at TrkB – a growth factor (neuropeptide) that supports growth of new synapses.
• Calcium influx induced intracellular LTP mechanisms: rapid insertion of new AMPARs + increased efficiency of existing ones.

How Do 5HT2A Agonism And NMDA Antagonism Both Lead To LTP? - NMDA Antagonism

• NMDA Antagonism: Blocked NMDA à more $Na^+$ at AMPA receptors / longer before Enough $Na^+$ that NMDA $Mg^{2+}$ block dislodges, allowing $Ca^{2+}$ influx
• $Na^+$ = sodium, $Ca^{2+}$ = calcium, $Mg^{2+}$ = magnesium
• BDNF = brain-derived neurotrophic factor
• TrkB = tyrosine receptor kinase B
• BDNF along with increased glutamate induces LTP by binding at TrkB – a growth factor (neuropeptide) that supports growth of new synapses.
• Calcium influx induced intracellular LTP mechanisms: rapid insertion of new AMPARs + increased efficiency of existing ones.

How Do 5HT2A Agonism And NMDA Antagonism Both Lead To LTP? - 5HT2A Agonism

• 5HT2A agonism: Increased stimulation à more $Na^+$ at AMPA receptors NMDA $Mg^{2+}$ block dislodges, allowing $Ca^{2+}$ influx
• $Na^+$ = sodium, $Ca^{2+}$ = calcium, $Mg^{2+}$ = magnesium
• BDNF = brain-derived neurotrophic factor
• TrkB = tyrosine receptor kinase B
• BDNF along with increased glutamate induces LTP by binding at TrkB – a growth factor (neuropeptide) that supports growth of new synapses.
• Normal LTP process – 5HT2A agonism: 5HT2A agonsm à NMDAR more efficient / sensitive to $Ca^{2+}$ à opens sooner: 5HT2A agonism increases BDNF mRNA levels* In hippocampus, parietal cortex, dentate gyrus +, but not globally*

Psychedelics & Plasticity: The Route to Novel and Personalised Treatments That Actually Work?

• Current work here in Exeter and elsewhere.

Psychedelic Assisted Psychotherapy

• The mechanism by which psychedelics act is through enhanced plasticity.
• Psychedelics can "prime" the brain for other therapeutic interventions to be more successful, such as CBT, talking therapy / counselling.

Psychedelic Assisted Psychotherapy

Psychedelic Assisted Psychotherapy: Let’s Look At Recent Clinical Trials…

• 1. MDMA-AP for PTSD (2021)
• 2. Psilocybin-AP for MDD (2023)
• 3. Ketamine-AP for AUD (2022)

Psychedelic Assisted Psychotherapy: MDMA + PTSD

• PTSD is typically treated with SSRIs sertraline or paroxetine - outcomes are very poor. – 40 to 60% don’t respond…
• Clinical trial of MDMA assisted psychotherapy.
• Chose MDMA because it’s known as an empathogen – brings about feelings of emotional openness
• Randomized trial:
  1. MDMA + psychotherapy (80–180 mg) or
  2. PLACEBO + psychotherapy

Psychedelic Assisted Psychotherapy: MDMA + PTSD

• Screening -> Enrollment -> Medication taper -> Experimental session -> Integration session -> Study termination
• 46 participants randomized to MDMA-assisted therapy and completed the first experimental session
• 44 participants randomized to placebo and therapy and completed the first participants experimental session

Psychedelic Assisted Psychotherapy: MDMA + PTSD

• CAPS5: Clinicial-Administered PTSD Scale
• SDS: Sheehan Disability Scale
• BDI-II: Beck Depression Inventory
• Strikingly effective…

Psychedelic Assisted Psychotherapy: Psilocybin + MDD

• Clinical trial of Psilocybin assisted psychotherapy for MDD.
• Double blind, randomized trial:
  1. Psilocybin + psychotherapy (0.215 mg/kg body weight – moderate dose) oor
  2. PLACEBO + psychotherapy
• MADRS and BDI scores were assessed to estimate depression severity

Psychedelic Assisted Psychotherapy: Psilocybin + MDD

• Flowchart: Pre-screenings -> Medical screenings -> Patients enrolled -> Baseline -> allocated to psilocybin/placebo group -> received allocated intervention -> completed study -> outcome

Psychedelic Assisted Psychotherapy: Psilocybin + MDD

• MADRS and BDI scores for Placebo and Psilocybin conditions over time.

Psychedelic Assisted Psychotherapy: Ketamine + AUD

• Clinical trial of Ketamine assisted psychotherapy for AUD.
• Double blind, randomized trial:
  1. three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy
  2. three saline infusions plus psychological therapy
  3. three ketamine infusions plus alcohol education
  4. three saline infusions plus alcohol education

Psychedelic Assisted Psychotherapy: Ketamine + AUD

• Study design flowchart showing visits for screening, randomization, therapy/education sessions with ketamine/saline infusions, and follow-up assessments.

Psychedelic Assisted Psychotherapy: Ketamine + AUD

• The ketamine plus therapy group shows the greatest percentage days abstinent and the placebo plus psychoeducation group the lowest.
• Treatment with three infusions of ketamine was well tolerated in patients with alcohol use disorder and was associated with more days of abstinence from alcohol at 6-month follow-up à 86% abstinence in six month follow-up

Things We Haven’t Talked About…

• 1. Is the “trip” a necessary part of the treatment, or could refined pharmacological compounds still provide the plasticity necessary without the trip?
• 2. How do we pick which psychedelics treat which psychiatric disorder; or is in a panacea?
• 3. Could there be negative effects to plasticity? – The role of Set and Setting as well as integration…

Group discussion points

1. Pros and Cons of make someone's brain more plastic / malleable
2. Is the psychedelic experience (hallucinations, out of body exp) necessary for the therapeutic effects of the drug?
3. For psychedelic therapy, what effect might the setting have?
4. What are the ethical implications for psychedelic treatment?

Summary

• Mechanisms of LTP / neuronal plasticity
• Serotonin and psychedelics
• Psychedelic assisted therapy