Lecture 17: Psychedelics Functional Properties

How do psychedelics act at a molecular level?

• Increased glutamate release onto cortical pyramidal neurons

• Activation of AMPA and NMDA receptors

• BDNF is released and binds to TrkB receptors

• TrkB activation leads to mTOR signalling

• Results in dendritic spine growth and synaptic strengthening

• Psychedelics act as positive allosteric modulators of TrkB receptor

• Preferentially enhances active synapses, promoting new and strengthened connectivity

What are the key challenges moving forward for psychedelic treatments?

• Promising effects seen, but issues with translatability from pre-clinical models to humans

• Effectiveness depends heavily on the animal model used and what is being modelled

  • Anxiety, fear, and PTSD animal models are limited

• Human studies rely on subjective self-reporting of symptoms before and after treatment

• Subjective scoring lacks robustness, reproducibility, and reliability

• Rodents cannot report subjective experiences, making direct comparison difficult

• Better objective and translational outcome measures are needed

How do psychedelics produce therapeutic effects?

• Promote neuroplasticity

  • Increase neuritogenesis, spinogenesis, and synaptogenesis

  • Modulate TrkB, mTOR, and 5-HT2A signalling pathways via BDNF upregulation

• Alter functional connectivity

  • Increase neural entropy and disrupt rigid, unhealthy thought patterns

  • Allow formation of new neural connections

• Psychedelic experience itself contributes to outcomes

  • Greater intensity correlates with stronger therapeutic effects

  • Associated features include suggestibility, wonder, ineffability, boundlessness, and noetic insight-

How do psychedelics alter brain activity and connectivity?

• Psychedelic effects can be examined across multiple levels of brain organisation

• High densities of 5-HT2A receptors are found in the frontal cortex, somatosensory cortex, and visual cortex

• Psychedelics act at 5-HT2A receptors to alter cortex-to-cortex connectivity

• At the cellular level, psychedelics increase excitability of layer 5 pyramidal neurons in the cortex

• Increased neuronal firing contributes to more variable and flexible brain activity (entropic)

• In the resting state, brain activity shows low entropy (organised and constrained)

• Psychedelics increase entropy, shifting activity toward a more disorganised state

• Increased entropy leads to global changes in brain connectivity

• Connections are disrupted, reorganised, and newly formed under the influence of psychedelics

How can fMRI be used to study the effects of psychedelics in the brain?

• Imaging measures brain activity through energy use and changes in regional blood flow

  • Increased neural activity (more active area) → increased blood flow to supply energy and nutrients

• It detects increased activity in neural circuits when brain regions work together

• Allow real-time monitoring of brain activity at rest or after psychedelic administration

• Enable comparison of different drugs and pharmacological treatment and their effects

• Resting-state imaging allows within-subject assessment of psychedelic-induced brain changes

How Can PET be Used to Study the Effects of Psychedleics on the Brain?

• Imaging shows high 5-HT2A receptor occupancy at higher doses of psychedelics

• Receptor occupancy maps correspond to brain regions rich in 5-HT2A receptors

• Provides translational validity between animal and human studies

• Intensity of psychedelic effects correlates with dose and 5-HT2A receptor occupancy (target validity)

• Allows for an association and correlation between the effects at target binding to occupancy to the effects

What are the principle of resting state fMRI?

• Resting-state fMRI measures brain activity when no task is being performed

• Allows identification of baseline brain network activity and disruptions

• Brain regions that are connected show synchronised changes in blood flow → functionally connected

• It enables the assessment of functional connectivity between brain regions

• Useful for examining how psychedelics alter brain networks and resting-state circuits

What Characterises Normal Resting State Connectivity in the Brain?

• At rest, the brain carries out housekeeping activities and is not engaged with a particular task → the brain returns things to normal (no task-specific processing)

  • Few pathways in the brain are active

• The default mode network (DMN) is active during conscious rest when not actively engaged in tasks

• Other functionally distinct networks are present at rest, including:

  • Attention / salience; Visual; Auditory; Sensorimotor; Executive control

• These resting-state networks contribute to the brain’s ordinary patterns and functional organisation

What is the Default Mode Network?

• Consists of high-level cognitive areas, including the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and inferior parietal regions (IPL)

• It is a task-negative network

  • Regions show strongly correlated activity during rest

  • Activity is reduced or suppressed during goal-directed cognitive tasks → ‘deactivated’

  • Circuitry is active when the brain is looking after itself and during the physiological “housekeeping” of the body, rather than when engaged in a particular task

• It is measured using fMRI → defined as a network of interacting brain regions that is active when a person is not focused on the outside world

How Do Psychedelics Need to Act to Be Use Theraputically?

• They do not need to alter how individuals do particular tasks, but need to act on the brain circuits that are at rest in anxiety and depression, which become abnormal

  • This is because in these disorders, individuals do not need to be engaged in a particular task to have the symptoms associated

What is Entropy in Brain Function

• The brain operates in a top-down approach via cortex-to-cortex interactions that feed into lower brain regions → organised

• Neuronal activity is highly synchronised, rhythmic, and ordered, allowing for synchronous behaviour (low entropy)

• Entropy refers to the level of organisation vs disorganisation in brain activity

  • At rest, the brain shows low entropy with stable, predictable patterns of activity

  • Psychedelics disrupt this synchronised and rhythmic activity, increasing disorganisation and randomness

• This increases entropy, reduces rigid top-down control and becomes more variable, allowing for new connections to form

• Increased entropy may help the brain escape rigid patterns of thinking, relevant to disorders characterised by rigid thinking

How Do Psychedelics Affect Brain Entropy and Conscious Experience

• They reduce rigid patterns of thinking, allowing for more flexible cognition (individual thinks differently)

• It allows us to have different connections, which enables new connections and the strengthening of pathways via neuroplasticity

• Entropy in neurodynamics is defined as a quantitative index of randomness or disorder in a dynamic system

  • High entropy = increased disorder and variability in brain activity

• Neuroimaging shows certain functional connections that can be associated with the primary state of consciousness and normal ‘modern-day’ walking consciousness

How Does Psyilocybin Disrupt to DMN and Increase Entropy

• Functional scanning shows that at rest, the DMN is active

• At rest, following psilocybin administration, there is an interference with the DMN, top-down processing becomes impaired, and there is a breakaway from normal brain functioning (when not actively engaged with a task

  • These changes are seen in the ventromedial and dorsolateral PFC and hippocampus

• This disruption to the DMN leads to increased entropy, increasing disorganisation and a break in the DMN and neural circuitries that work together, leading to a decreased power

What is Meant By A Decrease in Power

• Increased entropy is associated with decreased oscillatory power

  • Dependent on the frequency and the psychedelic being assessed

• Decreased power reflects changes in rhythmic neural activity

• When power changes are seen, this suggests altered brain activity patterns

• Changes in rhythmic activity across brain regions suggest changes in functional connectivity

  • Functional connectivity is ordered when neurons oscillate at a particular frequency in sync

How do psychedelics affect oscillatory power across frequencies?

• Effects depend on the frequency assessed

  • Alpha, beta, gamma, delta, theta

• Different psychedelics produce different effects at different frequencies

• LSD shows more pronounced effects due to its potency

  • Particularly large changes in alpha power

  • Changes occur across multiple frequencies

• Other psychedelics show less pronounced but similar reductions in power

• Psychedelics generally decrease oscillatory power

How Can Psychedelics Disrupt Rigiid Thinking

• They allow a breakaway from normal top-down control

• They disrupt the default mode network (DMN), which dominates at rest

• This allows changes in how the brain connects and communicates during the psychedelic experience

• Disorders such as depression, anxiety, addiction, OCD, eating disorders, and PTSD are associated with rigid patterns of thinking → dictate brain functioning and symptoms

  • These states are linked to low entropy

• Low entropy means brain activity is highly ordered and difficult to change → difficult to break pattern

• Psychedelics increase entropy, making the brain less constrained and more flexible, forming new connections

Why Are The Therapeutic Effects of Psychedelics Enhanced With Conselling

• Traditional drugs can reorganise disordered thinking to a limited extent

• Psychedelics can go further, producing stronger and longer-lasting reorganisation

• They break rigid thinking patterns, allowing old connections to weaken and new connections to form

• During psychedelic states, individuals are less constrained in their thinking

• Counselling provides guidance for alternative ways of thinking and a changed insight of self

• Together, psychedelics + counselling produce a combination effect

  • Psychedelics alone may have a limited impact

  • With counselling, they give rise to a more robust therapeutic effect

What is the Shake Up Effect Seen With Psychedelics?

• Imaging over time shows a network connectivity shake-up under the actions of psychedelics

• Brain regions that are normally connected at rest change their connectivity over time

  • Strongly connected networks become less connected

  • Loosely connected networks become more connected

• New connections can form due to the linking of different brain regions after psychedelic exposure

• These changes vary depending on the individual, their experience, disorder, and existing brain connectivity

• Overall, the brain becomes less constrained, allowing new patterns of thinking and behaviour to emerge

What is Ego Dissolution?

• A loss of ego and self-identity, with how the individual identifies self and their environment

• Change in perception when taking psychedelics → things once important in the environment become less important.

  • Allows flexibility in thinking and environment

  • Less concentrated on self and allows for the acceptance of differences.

• Functional connectivity changes underlie ego dissolution due to changes in connections which allow an individual to think differently

• This can occur alongside a psychedelic trip, resulting in changes in perception and becoming one with everything, and losing self

  • Weakened DMN connections allow individuals to feel “one with the environment.”

• Linked to REBUS theory (Relaxed Beliefs Under Psychedelics, by Robin Carhart-Harris).

What Are the Challenges With Studing Ego Dissolution?

• DMN is not the only network involved; multiple networks contribute.

• Entropy is difficult to measure and has not been studied enough; changes in resting-state activity provide evidence of psychedelic effects.

• Linking subjective feelings to brain imaging is difficult; predictions are vague and hard to test.

• Quantifying therapeutic effects requires additional measures beyond imaging.

How Do Pyscedelics Affect Cortico-Thalamic Processing and Sensory Filtering?

• 5-HT2A receptors are largely located in the cortex, especially layer 5 neurons.

• Layer 5 neurons project to the thalamus, which acts as a sensory filter and processes pain, visual, auditory, and subcortical input going to the cortex and modulates the activation of other cortical areas

• The thalamic reticular nucleus (TRN) is GABAergic and normally synapses with other thalamic nuclei, reducing their activity

• Psychedelics interfere with TRN activity, increasing activity reaching the TRN neurons and the cortex:

  • Hyperpolarisation of TRN neurons

  • Reduced normal oscillatory activity → weaker gating of sensory inputs

  • Reduced filter activity from the thalamus

  • More sensory information reaches the cortex → possible cross-modal effects (e.g., hearing a sound triggers a visual response)

• Explains the enhanced sensory perception and hallucinations during a psychedelic experience

Why Do Visual Hallucinations Occur in a Psychedelic Trip

• There is an interference in the TRN activity, which leads to an increase in the amount of activity reaching the thalamic nuclei and cortex

• There is greater stimuli and sensory information reaching the cortex that manifests as a typical symptom of a trip

• sensory stimulus may act to generate another sensory – e.g. hear a noise generates a visual response

Why are Models of Psychdelic Experience Not Mutually Exclusive?

• Models are not mutually exclusive as they both rely on changes in sensory processes occurring at the synaptic level, in the cortex, and in the thalamus.

• Supported by imaging findings showing increased global brain connectivity and function.

• Psychedelic effects vary depending on potency, dosage, and individual differences

Why is the Mystical Experince of Psychedleics Important?

• Hallucinations and changes in perception are linked to the therapeutic effectiveness of psychedelics.

• Therapeutic effectiveness is associated with the “mystical experience” that many seek recreationally.

  • Research is underway to understand why this is required for psychedelics to be therapeutic

• Debate exists on whether the mystical experience is required for therapeutic effects.

• Associated with prominent sensory changes occur at higher doses, which led to microdosing, which aims to avoid mystical experience while retaining some therapeutic benefit.

• Hallucinogenic/perception-altering experience correlates with long-lasting therapeutic outcomes.

How is the Mystical Experince of Psychedelics Being Used in Therapy?

• Therapy involves a number of high-dose psychedelic sessions, usually before, during, and after psychological sessions.

• Aims to support a transformative psychological experience.

• Higher doses → greater mystical experience → more robust, longer-lasting therapeutic effects.

• Pre-session preparation and counselling guide the patient on what to expect.

• Counsellor prepares individuals before and is present during the session, either monitoring or counselling the patient

How Can the Mystic Experience Be Measured

• Quantified using questionnaires

  • Not short questions

  • Leading in nature

• Examples include

  • MEQ  “mystical experience questionnaire” (Pahnke and Richards 1966)

    • The first to be described

  • Questionnaies have been built on or are modified versions of MEQ

    • M scale  (Hood Jr, 1975)

    • ASC “ altered states of consciousness questionnaire” (Dittrich 1998)

How do ASC scores relate to clinical outcomes 5 weeks post-psychedelic therapy?

• Spider web maps numerically visualise and correlate changes in ASC responses and therapeutic effects.

  • Responders: Higher scores in most ASC domains (especially spiritual experiences, blissful state, insightfulness).

  • Non-responders: Lower scores; poor therapeutic effect.

• No difference between groups in anxiety, cognition, impaired control, or disembodiment.

• Interpretation is tricky as the links between ASC changes and theraputic outcomes are not fully clear.

In psychedelic therapy, what is the debate between neuroplasticity and mystical experiences, and what is currently understood?

• Debate as to whether neuroplasticity or mystical experiences drive therapeutic effects.

• Likely both contribute, with the strongest therapeutic effects when the full psychedelic experience occurs.

• Connectivity changes suggest mystical experiences may occur at lower doses, but extensive neuroplasticity and behavioural changes often require higher doses.

Can non-hallucinogenic compounds replicate the therapeutic effects of psychedelics?

• Compounds like Tabernanthalog (non-hallucinogenic 5-HT2A agonist) are being tested.

• Evidence is variable and not fully convincing.

• Some research (Olson 2021) suggests neuroplasticity alone can produce enduring changes in behaviour and mood.

What is known about psychedelic use for addiction treatment?

• Evidence shows a therapeutic potential, but mechanisms are not fully understood.

• Studies date back to the 1970s (e.g., LSD for alcohol dependence).

• Positive effects in treat addiction linked to mystical experiences, especially with psilocybin.

• Research is limited, carried out on a small scale, with the AUD patients recruited being variable, making interpretation challenging.

  • Conflicting effects seen → lack of rigorous clinical research

How do specific psychedelics affect addiction behaviours?

• Ibogaine for AUD reduces withdrawal and cravings, decreasing drug-seeking behaviour; median abstinence ~5.4 months after a single dose, 8.4 months after multiple doses.

• Psilocybin: Shows promise for alcohol and cocaine use disorder; therapeutic effects may require a mystical experience.

• Some psychedelics produce sustained effects over time as opposed to any current pharmaceutical treatment but study sizes are small and patient variability complicates conclusions

What were the key features and findings of the psilocybin study for alcohol dependence?

• Design: Open-label study, 10 participants meeting DSM-5 criteria for alcohol dependence.

• Intervention: Two oral psilocybin sessions within a 12-week motivational enhancement therapy program.

• Outcome: Large and sustained reduction in drinking days and heavy drinking days compared to baseline.

• Duration of effect: Sustained for up to 6 months after just two doses

What are the key properties and limitations of ibogaine for therapeutic use?

• Natural plant extract used in Indo-rituals

• Shown success in preclinical and some clinical studies.

• Difficult to synthesise and cultivate; not widely available.

• Has cardiovascular side effects due to 5-HT2B antagonism - no directly developed as a theraputic

• Not suitable for commercial drug development.

How does Tabernanthalog (TBG) improve on ibogaine for drug development?

• Synthetic, non-hallucinogenic analogue of ibogaine; does not produce head-twitch in animals.

• Potent 5-HT2A agonist, but avoids 5-HT2B antagonism, preventing cardiovascular effects.

• Lacks opioid activity.

• Demonstrates that therapeutic effects can occur without psychedelic experiences

What were the effects of Tabernanthalog (TBG) on ethanol consumption in preclinical rodent studies?

• Rodents given a choice of alcohol vs. water; TBG administered (paired with alcohol for 48 hours); again given a choice of alcohol vs. water

• Results: TBG decreased alcohol intake strongly in the first 2 days, but effect was lost by day 5.

• No change in general drinking behaviour → no sedative effects.

• Slight, non-significant reduction in alcohol preference.

• Suggests TBG has a mild, short-term effect on alcohol consumption → positive effect but not ideal for therapeutic application; unclear if lack of hallucinogenic properties limits its efficacy.

What are the main issues plaguing psychedelic research?

• Small study sizes, especially in the 1960s–70s.

• Different methodologies

  • No robust scientific collection and analysis of results - hard to measure mystical experiences or consciousness.

• Variable doses/routes and regimes: difficult to determine optimal dosing strategies for maximal therapeutic effect.

• Control challenges: difficult to design proper placebo/control conditions for psychedelics.