Lecture 6: Comeback of Psychedelic Renaissance - Enhancing mood & cognition

History

• Probably oldest drugs known to man (evidence for use in about 10.000 BC)
• Psychedelic = “mind revealing”
• Widely found in nature:
  • Psilocybin (magic mushroom)
  • DMT (found in every human)
  • Mescaline (contained in cactuses)
  • 5- MEO DMT (found in certain toads)…
  • LSD: only chemically extracted psychedelic
• LSD was discovered by Albert Hoffman (1943)
• More than 40,000 patients were administered LSD alongside therapy between 1950 and 1965. Non-toxic, non-addictive and effective clinical tools
• Understanding of mental illness: models psychosis Psychological transformation in psychotherapy Military use
• 1953 -Similarity found between serotonin in the brain and LSD - the birth of Neuroscience (Dr Woolley)
• 1960’s Contra-culture - Vietnam War anti-millitary attitudes
• 1970 Controlled Substances Act: psychedelics scheduled as illegal
• Renamed as psychotomimetics/halucinogens a suggesting that they are resembling psychosis (Hoffer, 1967).

The psychedelic experience

• Mood: high arousal
• Perception: geometric visual patterning morphing, abstract imagery
• Cognition: unconstrained cognition dream-like states loss of Ego/loss of sense of self divine/spiritual presence

How do these drugs affect the brain?

• Most important receptor for all class of psychedelics: serotonin 2A – the more potent the drug, the more sticky it is with this receptor
• If 2A receptor is excited by LSD, rats learn faster
• 5-HT2AR agonism stimulate neuroplasticity in the hippocampus and the neocortex
• Expression of 2A receptors: mostly higher cortical areas (layer V of grey matter)
• Increase of serotonin will increase secretion of GABA (inhibitor) to Thalamus
• Thalamus: in charge of filtering out irrelevant information from the outside world
• Psilocybin decreases activity in higher cortical areas but brain connectivity is high (parts of the brain are more connected)
• In a psychedelic state: more flexible neurological traffic

Default Mode Network

• Highly interconnected network
• Active when you daydream, think of the past/future, in self-chatter
• Consumes 40% more glucose than any other part of the brain
• If this network is disintegrated, there is a feeling of losing sense of self

Entropic brain theory

• Our brain throughout development always tries to minimize uncertainty
• As children, we don’t put things into coherent categories yet, so we think more things are possible
• In older age, we are better at predicting reality, but it can lead to rigidity
• Our consciousness is positioned between flexibility and resistance
• In our sleep or in psychosis: more flexible, unconstraint thoughts
• Psychedelic state: regression to more child-like state – curiosity, surprise, more delusional etc
• Increasing flexibility (chaos) benefit disorders with rigid pattern of behavior (OCD, Depression or Addictions)

Why are Psychedelics clinically interesting?

• Griffiths et al. (2006):  67% said the psychedelic experience was in the top 5 most meaningful experiences in their life,  62% had complete mystical experience
• Increase in the personality trait “Openness” MacLean (2011)
• 80% abstinence from smoking because of psychedelics(Johnson et al. 14)
• Decreased drinking at 9 months follow-up  (Bogenschutz et al. 15)
• Reduction of symptoms of OCD (Moreno et al. 2006)
• Decreased anxiety at 12 months in life threatening illness (Gasser et al. 14)
• Reduced distress & suicidality in US population (Hendricks et al. 15)
• Decrease in depression  (Rucker, 2016)

Basic mechanisms for SSRI vs Psychedelics

• Function of serotonin remains elusive
•  5-HT1A and 5-HT2A two most prevalent serotonin receptors
•  SSRI ➔ 5-HT1A reuptake blocking
• Psychedelics ➔ increase in signaling of 5-HT2A neurons
• 2A signaling downregulates 5-HT2AR receptors and thus ➔ less anxiety and improved general well-being during the post-acute ‘after glow’
• SSRIs: passive coping – numbing feelings by making you more tolerant to stress
• Psychedelics: active coping – adaptive change
• 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity – passive coping
• 5-HT2AR-mediated plasticity – applied when adversity reaches critical point and adaptation and flexibility is required – active coping
• Psilocybin reduces reaction to threatening images, and to feeling hurt when socially excluded, while increasing empathic feelings

Overprediction

• Sensory input is not essential for perceptual experience
• Brain will try to extract meaningful signal from environment
• Brain predict what is happening based on our previous experiences.
• Hallucinations are a result of prediction error imposed on noisy data.