Psychedelics Flashcards
What does ‘psychedelic’ mean?
‘mind manifesting’ in Greek
How are psychedelics classified (2)?
- Classical (Serotonergic) Psychedelics
- Non-classical (Non-) Psychedelics
What are the properties of classical psychedelics + 4 examples?
-structural similarities to serotonin
-activates serotonin 2A receptors
-similar but unique effects on cognition, perception, sensory processing
-Psilocybin, LSD, DMT, mescaline
What are the properties of non-classical psychedelics +2 examples
-structurally dissimilar to serotonine
-don’t activate serotinin 2A receptors
-alterations in cognition, perception, sensory processing
-Ketamine, MDMA
MOA and effects of Ketamine and MDMA
Ketamine:
-glutamate NMDAR antagonist that indirectly activates excitatory AMPAR signalling
-dissociative effects
MDMA:
-release serotonin/dopamine via transporters
-stimulant/’ecstasy’ effects
How do psychedelics mainly work?
-First pass metabolism in liver (+sometimes GI tract) by cytochrome CYP450 enzymes
Which neurotransmitters are mainly responsible for excitatory vs inhibitory neurotransmission?
- Excitatory: Glutamate
- Inhibitory: GABA
What are the MOA of the main neurotransmitters?
- Glutamate: activate glutamate AMPA+NMDA receptors -> neuronal depolarization (ON)
- GABA: activate GABAA receptors -> neuronal hyper-polarization (OFF)
Glutamate/GABA: fast ionotropic neurotransmisison via ligand-gated ion channel receptors
What is the neurotransmitter pathway of psychedelics?
Neuromodulators: Serotonin (5HT) Dopamine (DA), Norepinephrene (NE)
What type and MOA of receptor is used for neuromodulators?
G-coupled protein receptors (GPCR)
-associated w/ slower changes in intracellular signalling
1. NT binds
2. G-protein activated
3. G-protein subunits or intracellular messengers modulate ion channels
4. Ion channel opens
5. Ions flow across membrane
Which specific neuromodulators do classical psychedelics target?
Activates 5-HT receptor subtypes (mainly 2A) of serotonin
Partial agonists (not as effective as 5HT)
What are the 2 signalling pathways of classical psychedelics?
- 5HT2A canonical signaling
-excitatory, Gq-coupled
-prolonged activation recruits B-arrestin -> desensitization, internalizaiton, degradation -> drug tolerance - Non-canonical signalling
-arrestin-bound receptors regulate unique downstream cascades (cell growth, proliferation, angiogenesis)
How is serotonin activity terminated?
- Monoamine oxidase: removes serotonin (5HT) from synapse following release via neurotransmission/psychedelic activation
- 5HT reuptake from synapse: by specific monoamine transporter, SERT
What are the causes of major depressive disorder (MDD)?
-monoamines (serotonin deficiency)
-genetics, stress
-emerging theories (impaired glutumate neuroplasticity)
What is an emerging psychedelic treatment for depression?
Ketamine: clinical discovery that low-dose has robust antidepressant effects (hrs to weeks)
What are the 3 neuroplasticity processes at excitatory synapses?
- Neurogenesis (rare in adults)
- Synaptic plasticity
- Structural plasticity
What is synaptic plasticity?
Activity dependent strengthening/weakening of:
1. synaptic transmission
2. long-term potentiation (LTP)
3. long-term depression (LTD) - cell substrates of learning/memory in the brain)
What is structural plasticity?
Physical modifications of:
-axonal/dendritic branches
-spine morphology
-synaptic numbers that mediate adaptations to environmental stimuli (learning events, pathophysiological processes) via synaptogenesis/synaptic atrophy
What is the major site of pathogenesis?
- Medial prefrontal cortex (mPFC)
- Hippocampus (HPC)
Explain the pathogenesis of depression
Stress/Susceptibility -> Dysregulated synaptic/neural plasticity-> Maladaptive regional sturctural plasticity+ altered neurocircuit activity/connectivity, neuronal atrophy -> depression symptoms (altered stress response, cognition, emotion)
What is the mechanism of ketamine and classical psychedelics in neuroplasticity?
Promote synaptic homeostasis and adaptive rewiring of pathological circuitry -> Reversal of stress-induced structural/function deficits
How do neuromodulator neurotransmitter pathways contribute to the therapeutic effects of classical psychedelics?
Transient window of increased plasticity
1.Activate 5HT2A receptors -> downstream cascades through GPCR signalling
2.Increased extracellular glutamate release -> neuron excited + synaptogenesis in mPFC/HPC
3. New connections + patters of functional connectivity across the brain
4.Enhanced window of neuroplasticity for adaptive rewiring, structural changes
How is the head twitch response used to measure psychedelic drug action?
Activate 5-HT2A via acute psychedelic administration increases frequency of rodent head twitch
Over 30 different psychedelics correlated b/w specieis = predictive validity
What are important research and clinical considerations of psychedelic therapy?
(key factors, treatment model, major hurdles)
- Key factors: dose, set, setting
- Treatment model: screening, preparation, psychedelic-assisted therapy, integration, reporting
- Major hurdles: funding, regulations, methods, ethics, stigma
What are some current psychedelic research limitations?
-small cohorts/sample size
-mostly short-term studies
-no gold standard for placebo control
-recruitment bias
-cost/access/equity/scalability
-appropriate safety assessments
-appropriate efficacy endpoints
Why are psychedelics considered non-addictive?
-tolerance/cross-tolerance (decreased drug effects w/ repeated use)
-use patterns (sporadic/recreational)
-long-lasting ‘trip’
-potential modulation of limbic system (5HT2A activation causes changes in phasic dopamime release -> affect rewarding aspects of drug abuse)
