Lecture 15: Psychedelics

Question 1

What is a psychedelic experience?

Answer 1

• Increased sensory perception and illusionary changes
• **Synaesthesia
• Enhanced mental imagery
• New associations and meanings of relationships and objects
• Access to inner thoughts & feelings that are usually repressed
• Ego dissolution
• Increased affectivity
• Dream-like experience, but in clear consciousness
• Full awareness of self & good memory of the experience

Question 2

Lysergics

Answer 2

• Drug
  
  • lysergic acid diethylamide(LSD)
  • psilocybin
  • mescaline
  • dimethyltryptamine
• Primary target: 5-HT2 receptor agonists
• Potential use: depression, addiction

Question 3

Entactogen

Answer 3

• Drug: MDMA (ectasy)
• Primary target: monoamine releaser
• Potential use: PTSD?

Question 4

Dissociative

Answer 4

• Drug
  
  • Ketamine
  • Phencyclidine
• Primary targets: NMDA receptors
• Potential use: depression (only ketamine)

Question 5

Who is Albert Hoffman?

Answer 5

First person to synthesize LSD in 1938

Question 6

What is 5-HTR?

Answer 6

• Serotonin receptor
• GPCR that binds to serotonin (5-hydroxytryptamine, or 5-HT)
• Play various roles in modulating neurotransmission and are targeted by different drugs for therapeutic purposes.

Question 7

What effect did mutations in the 5HT2B receptor have on LSD binding?

Answer 7

Mutations in the 5HT2B receptor reduced the amount of time the LSD molecule spent inside the receptor, indicating less effective trapping.

Question 8

How did the EL2 region of the 5HT2B receptor influence LSD binding?

Answer 8

The EL2 region acted as a lid, trapping the LSD molecule in the binding pocket of the receptor. Mutations causing increased lid movement resulted in reduced trapping of LSD.

Question 9

What happens to brain activity when individuals are given LSD or psilocybin?

Answer 9

• Expansion of activity in certain networks and nodes, with flattened networks
• Different brain regions communicate more extensively, providing a sense of self
• Psilocybin leads to the dissolution of normal brain communication patterns → communication between regions that don’t typically interact, resulting in ego dissolution, which can be quantified.

Question 10

What changes occur in brain activity when individuals are administered LSD or psilocybin, and what effects do these substances have on neural networks?

Answer 10

• Individual nodes of activity and an expansion of network activity in adjacent regions. This leads to flattened networks and communication between different brain regions that may not typically interact.
• Psilocybin, in particular, facilitates communication between regions of the brain that do not normally communicate,
  
  • Results in ego dissolution (evaporation of the sense of self) which can be quantified.

Question 11

How does MDMA affect brain networks and what implications does this have for conditions like PTSD, depression, and anxiety?

Answer 11

• MDMA disrupts brain networks similarly to LSD and psilocybin.
• In individuals with PTSD, there is often excessive rumination and repetitive thinking. MDMA reduces activity in brain regions associated with rumination, such as the prefrontal cortex and posterior cingulate cortex.
• This reduction in activity can alleviate symptoms of PTSD, depression, and anxiety by reducing rumination and promoting contextualization of traumatic memories.
• Additionally, MDMA increases interactions between the amygdala and the hippocampus, which may facilitate processing of traumatic events and promote emotional healing.

Question 12

How does MDMA affect the behavior of octopuses in terms of sociability?

Answer 12

• In a study conducted by Edsinger and Dolen in 2018, it was observed that MDMA (3,4-methylenedioxy-N-methylamphetamine) administration to solitary octopuses increased their sociability.
• When given a choice between interacting with an inanimate object or another octopus of the same species, octopuses in their normal state preferred the object.
• However, after receiving MDMA, the octopuses exhibited more social interaction and spent more time with the other octopus, indicating an enhancement of sociability.
• Additionally, MDMA was found to enhance feelings of empathy in octopuses toward others.

Question 13

How do PCP and ketamine contribute to the understanding of schizophrenia?

Answer 13

PCP and ketamine induce positive, negative, and cognitive psychotic symptoms in humans, such as auditory hallucinations and thought disorders.

Question 14

How does disruption of glutamatergic transmission relate to schizophrenia?

Answer 14

• Disruption of glutamatergic transmission is observed in schizophrenia.
• Evidenced by reductions in the expression of NMDAR subunits, such as NR1 mRNA and NR1 protein, in individuals with schizophrenia. Genetic studies also show disruptions in NMDAR-associated signaling pathways, such as the N2RA subunit.
• Increasing the concentration of co-agonists, such as D-serine, has shown benefits in individuals with schizophrenia.
• Individuals who develop psychosis have antibodies to the NMDA receptor → a reduction in NMDAR signaling, similar to the effects of PCP and ketamine, which are NMDA receptor antagonists.

Question 15

What are the characteristics and uses of ketamine?

Answer 15

Ketamine, introduced as an IV anesthetic in 1970, exhibits several unique characteristics and applications:

1. Dissociative Anesthetic
2. Rapid Induction and Wide Safety Margin
3. Pre-Hospital and Battlefield Use
4. Pediatric Anesthetic
5. Bronchodilator
6. Anti-inflammatory and Neuroprotective
7. Primary Anesthetic in Developing Countries
8. Veterinary Medicine

Question 16

How does ketamine affect connectivity between brain regions associated with depressive symptoms?

Answer 16

• Ketamine reduces connectivity between brain regions that support depressive-like symptoms.
  
  • Specifically, there are reductions in connectivity between the posterior cingulate cortex and the prefrontal cortex, as well as between the posterior cingulate cortex and other regions.
• Leads to less rumination and dwelling → antidepressant effects.
• Fewer connections within the affective network → less reinforcement of negative emotions and mood in individuals treated with ketamine.

Question 17

What are the effects of ketamine on neuronal activity and synaptic processes?

Answer 17

• Ketamine administration leads to increased glutamatergic activity and excitation in certain brain networks. Results in more glutamate release → increases the production of neurotrophic factors such as BDNF (brain-derived neurotrophic factor).
• Ketamine induces synaptogenesis, changes in synaptic strength, and neurogenesis → rearrangement of synaptic networks and potentially enabling individuals to rewire away from self-loathing networks associated with depression.

Question 17

How does ketamine affect neuronal circuits in the brain?

Answer 17

• Ketamine, as an NMDA receptor antagonist, primarily targets inhibitory NMDA receptors or neurons at low doses.
• This preferential inhibition of inhibitory neurons, particularly GABAergic neurons, helps stabilize the brain from ruminative and self-doubting networks commonly associated with depression.