Psychedelics Flashcards
Psychedelic drugs
A subset of psychoactive drugs
‘psychedelic’
latin for ‘mind-manifesting’
History of psychdelics
- 3,700 BC: Peyote was used by native Americans
- 1,500 AD: psilocybin used by Aztecs
- > 1,000 AD: DMT use
- 1938: Synthesis of LSD by Albert Hoffman
- 1943: Marketing of LSD as Delysid for a range of psychiatric disorders
Delysid
The marketing of LSD for a range of psychiatric disorders including ‘anxiety states’ and ‘obsessional neuroses’
- repeated dosing, with doses ranging from 25µg to 400µg
- thought to elicit the release of repressed memories and provide mental relaxation
Drugs that counteract psychedelic experience
- Phenothiazine tranquillisers (eg: chlorpromazine)
- Barbiturates (eg: thiopental)
- 5HT2A antagonists
5HT2A distribution
- widespread throughout the brain
- densely expressed in PFC, posterior cingulate, and visual cortex
5HT2A mechanism
A Gq-coupled GPCR
- increases phospholipase C
- increased calcium release from intracellular stores
- enhanced neurotransmission in pyramidal neurons via promoting active phosphorylated state of ion channels
+
- BDNF-induced neurogenesis
- due to kinase activation and intracellular signalling
Other neurotransmitter affected by psychedelics
Oxytocin
- increased following LSD, mescaline, and psilocybin
Effects of psychedelic administration
- Visual hallucinations
- Changes in sensory processing
- Synesthesia
- Altered emotional processing
- Ego dissolution
- Altered sense of time
How do psychedelics alter sensory processing?
Normally, sensory processing occurs through top-down processing, whereby our brains fill in our perception of the environment based on sensory information and previous experience. This process is mediated by the thalamus, which acts to integrate all afferent inputs (including sensory and other important information) and filters out non-salient information.
Psychedelic administration causes significant agonism of 5HT2A receptors in pyramidal cells of the cortex, resulting in an increased excitability. This results in increased glutamate release onto downstream GABAergic neurons, resulting in a disinhibition of the thalamus through basal ganglia pathways.
This disinhibition can be thought of as a ‘lack of sensory gating’ and thus prevents top-down processing.
Hollow mask illusion
An illusion based on our tendency to see faces despite faces being absent, due to the salience of faces for our survival.
Involves the rotation of a hollow mask in two directions.
- Normally cannot distinguish which direction the mask is rotating
- People on LSD could correctly tell when rotation switched
Ego-dissolution
The loss of the ‘sense of self’ which is defined proprioceptively, temporally, spatially, and psychologically.
- rubber hand experiment shows how ‘self’ is in part an illusion
Correlated with improvements in depression, anxiety, and addiction
The default mode network
The DMN is composed of the prefrontal cortex, posterior cingulate cortex, as well as other regions. These regions are functionally connected through shared activation during ‘self-directed’ thought such as autobiographical memory and future planning which has been shown through fMRI.
What is the effect of psychedelics on the default mode network?
The effect of psychedelics on the DMN is complex, but generally involves a decreased integrity and connectivity of the DMN with other regions.
- there is also increased activity in the visual network.
Decreased DMN integrity is correlated to increasing ego-dissolution, and this has been further correlated with low depression scores after ayahuasca treatment.
Problems with current state of anti-depressant treatment
Anti-depressants have questionable efficacy, as the treatment of mild to moderate (but not severe) depression has been shown to be largely mediated by the placebo effect.
- Not effective for everyone
- Side effects
- Long time to produce efficacy (3-4 weeks) despite relatively fast pharmacological changes
What are the mechanisms underlying the therapeutic potential of psychedelics for depression?
- Neurogenesis
Psychedelics promote neurogenesis- the formation of new synapses- through action on 5HT2A. This also occurs in anti-depressant treatment, and has been correlated to reduced depressive symptoms - Behavioural catalysts
Psychedelics have been shown to increase open-mindedness, allowing individuals to break free of harmful thought patterns. This is used therapeutically though combination with cognitive behavioural therapy, which may be aided by the oxytocin release induced by psychedelics which may increase the patient-therapist relationship.
Clinical trials
(Carhart-Harris et al., 2021)
- Psilocybin reduced depression scores more than Escitaprolam, but not significantly
- Psilocybin increased overall wellbeing scores over Escitaprolam.
(Goodwin et al., 2022)
- three doses (1mg, 10mg, 25mg)
- 20% remission of depression at 12 weeks following 25mg psilocybin treatment
(Von Rotz et al., 2022)
- Psilocybin treatment for moderate depression resulted in remission of 50% of patients compared to 14% of placebo
- 10 fold reduction of depression scores compared to placebo
- Therapeutic effect not correlated to subjective drug experience
+/- Psychedelic therapy
+: avoids multiple dosing, has instant effects, minimal side effects
-: $$$ therapy, requires specially trained psychiatrists, exclusion of those with history of psychosis
Harm potential of psychedelics
- Low drug harm (Nutt) due to high therapeutic index and tolerance preventing physical dependence (likely would change if use became widespread)
- HPPD
- Anecdotal reports of psychosis
- Full agonists (NBOmes) have been known to cause toxicity and death
