11 Psilocybin Flashcards
What is Psilocybin?
- psychedelic prodrug, produced by more than 200 species of fungi (easily mistaken for other mushrooms, flesh turns blue when bruised, DNA-based approach best bet for identification)
- consumed in therapeutic settings, recreationally
- available fresh, treated/preserved, as dry powders or capsules
- Registry of Toxic Effects of Chemical Substances: therapeutic index of 641
- only few countries where (partially) legal/decriminalized
History of Psilocybin
- 6000-7000 years ago: 1000s of years of religious use by Old-World countries
- 1579: Florentine Codex - first documentation of spiritual and divinatory uses in Mesoamerica
- 1957: R. Gordon Wasson publishes “Seeking the Magic Mushroom”
- 1959: Albert Hofmann purifies psilocybin from dried mushroom sample
Research Value of Psychedelics
- controlled studies provide major new insights into nature of the mind and how it arises from brain activity
unique scientific value they offer rests on their ability to: - selectively target processes critical for the maintenance of normal waking consciousness (-> how the components of the brain give rise to global phenomena)
- studied at a range of epistemological levels (from pharmacology to psychopathology)
Measuring Psychological Effects of Psychedelics
- acute psychological effects produced by classical psychedelics most reliably and commonly measured by 5-Dimensional Altered States of
Consciousness Rating Scale (5D-ASC) - scale is suited to depict alterations in waking consciousness including changes in mood, perception, experience of the self and the environment, etc.
- intensity of alterations of consciousness and perception is dose dependent
5 subscales and 11 lower-order scales - oceanic boundlessness (derealization and depersonalization, change in sense of time and emotions, unity, spiritual experience, blissful state)
- anxious ego dissolution (ego disintegration, dysphoric mood states, disembodiment, impaired control of cognition, loss of self-control
- visionary restructuralization (complex/elementary imagery, changed meaning of percepts, audio-visual synesthesia
- auditory alterations (changes to acoustic phenomena)
- reduction of vigilance (states of drowsiness, impairment of alertness)
Acute Psychological Effects of Psilocybin
psilocybin increases
- oceanic boundlessness strongly (blissfulness, unity, spiritual experience)
- visionary restructuralization strongly (complex/elementary imagery, changed meaning of percepts, audio-visual synesthesia)
- reduction of vigilance
- anxious ego dissolution slightly
no auditory alterations
Psilocin
- the active metabolite of psilocybin
- psilocybin is rapidly dephosphorylated to psilocin (psychoactive, hallucinogenic)
- half-life: 1-3 hours
- structurally very similar to serotonin (5-HT)
- particularly high affinity to 5-HT_2A receptors (5-HT_2A agonist)
- in rodents, behavioural equivalent of psychedelic effects seen in humans is head twitch response (5-HT_2A knock-out mice -> HTR abolished, prior 5-HT_2A antagonism -> HTR abolished)
Receptor 5-HT_2A - key points
- G protein-coupled receptor (GPCR)
- esp. abundant on excitatory PFC pyramidal neurons in layer V
- agonism linked to hallucionogenic effects
Receptor 5-HT_2A - signaling cascade
psilocin binds to receptor 5-HT_2A triggering:
- Galpha_q-protein coupled activates Phospholipase C (PLC)
- this cleaves PIP_2 into IP_3 + DAG
- IP_3 leads to Ca2+
- Ca2+ + DAG co-activate Protein Kinase c -> Arachidonic acid (AA)
Psilocin - Pharmacology (Tolerance)
rapid tolerance, but no dependence
- repeated administration leads to downregulation of 5-HT_2A receptors
- unlike LSD, no significant effect on dopamine receptors (anti-addictive effects?)
- cross-tolerance with other psychedelics
affects a number of other serotonin receptors (5-HT_2C, 5-HT_1A)
- some subjective symptoms remain after coadministration psilocybin + 5-HT_2A antagonist
complete pharmacological profile is not well-established
System-Level Analysis of Psilocybin
CBF, BOLD signal, functional connectivity and oscillatory power are decreased in brain regions that are normally:
- highly metabolically active
- functionally connected
- synchronous/organzied in their activity
-> dysregulated global brain function triggered by 5-HT_2A receptor activation
decreases are localized to high-level association cortices (vs. increases in visual cortex), including key regions of Default Mode Network (DMN) and subcortical structures (e.g. putamen and thalamus)
What is the Default Mode Network?
- set of widely distributed brain regions in the parietal, temporal and frontal cortex
major hubs include: - medial prefrontal cortex (mPFC)
- posterior cingulate cortex (PCC)
- precuneus
- angular gyrus
suspended/suppressed activity during goal states (heightened activity in task-negative states)
characteristics of Default Mode Network
- houses dense expression of 5HT_2A receptors
- DMN regions receive more blood flow and consume more energy than other brain regions (reasons for this poorly understood; some suggest it to be the physical counterpart of the “narrative self” or “ego”, much of which is implicit)
- centers of dense connectivity (particularly PCC) serve as important connector hubs for information integration and routing
- known to house the highest # of cortico-cortical connections
- engaged in higher-level metacognitive operations such as self-reflection, ToM , and mental time travel (self-referential activity)
- RSFC correlates positively with ratings of depressive rumination (activity in the mPF node of DMN is reliably elevated in depression)
Psilocybin and Default Mode Network
consistent, acute disruption in RSFC within DMN
- acute decrease in blood flow within nodes of the network
- decoupling between key nodes such as mPFC and PCC (rebalancing of hierarchical activity in distributed high-level modes)
observed desynchronous and disorganized activity overall (deactivation has profound implications for consciousness
- reduced FC is associated with positive states of ego dissolution
- correlated with subjective experiences of positive disintegration of self
self-organized activity in DMN -> emergence of coherent sense of self, birth of ego
unorganized, unpredictable, disturbed interconnectivity -> death of ego
Psychedelics and Brain Connectivity
- seem to increase between-network connectivity
- marked by unique shift in neural connectivity to more interconnected global network
- tentatively hypothesized to result in mind less constrained, more flexible, less self-referential and egoic
REBUS Model (Relaxed Beliefs under Psychedelics)
- provides a unified theoretical account of acute psychological effects and mechanisms through which they lead to positive therapeutic outcomes
- is informed by hierarchical predictive coding
- basic idea: psychedelics serve to relax the precision weighting of previous beliefs -> under psychedelics, brain is less constrained by pre-existing structural priors -> extend free ability for the brain to create a greater array of FC patterns and networks
-> less of an effect on cognition -> can enable revision of pathologically overweighted priors -> reappraisal of maladaptive beliefs about the self and the world -> assisting in long term therapeutic change
