How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks

Introduction to Psilocybin

• Psilocybin is a psychedelic that modifies the psyche and changes our level of consciousness
• Changes perception of the outside world and internal world, memories, thoughts, and feelings
• Can fundamentally change these aspects even after the psychedelic experience
• Growing excitement for its application in treating mental health issues like depression, alcohol abuse, addiction, OCD, and eating disorders

Other Psychedelics

• LSD, DMT, 5‑MeO-​​DMT, and MDMA (not a classic psychedelic but considered one in a general sense)

Therapeutic Approaches

• Proper psilocybin therapeutic approaches focus on the post-​​experience period
• Positive changes occur after the session, including hallucinations and changes in thought patterns
• Conditions during the psilocybin journey impact the therapeutic outcome (e.g., eyes open/​​closed, music played, dosage level)

Safety Issues and Considerations

• Young people (25 or younger) should consider their brain’s natural neuroplasticity before using psilocybin
• Dosages for those on antidepressants
• Risk for psychotic episodes for those with a propensity for psychosis or close family members with psychiatric conditions

Psilocybin and Serotonin

• Psilocybin is a tryptamine, closely resembling serotonin in chemical structure
• Serotonin is a neuromodulator, affecting the activity of other neurons and neural circuits
• Serotonin is involved in satiety, mood regulation, pleasure, motivation, and many other functions
• Serotonin receptors have various functions, including changing neuron activity, releasing growth factors, and altering gene expression

Psilocybin vs. SSRIs

• Psilocybin has shown to outperform standard therapy and SSRIs (Selective Serotonin Reuptake Inhibitors) in providing depression relief
• SSRIs increase serotonin transmission nonspecifically, leading to side effects and mixed results
• Psilocybin’s specific binding to the serotonin 2A receptor allows for more targeted effects

Key Takeaways

• Psilocybin’s chemical similarity to serotonin and its selective binding to the serotonin 2A receptor make it a promising therapeutic tool
• Its effects on mood, pleasure, and creativity are linked to its activation of the serotonin 2A receptor
• Understanding the serotonin 2A receptor and its role in neural circuitry is crucial for optimizing psilocybin’s potential benefits

  Serotonin 2A Receptors and Psilocybin

• Serotonin 2A receptors are located in multiple brain regions, including the neocortex 
  • High expression in the prefrontal cortex, which is involved in understanding context and adapting behavior
  • Also found in areas associated with sensation and perception, such as the visual cortex
• Psilocybin binds strongly to serotonin 2A receptors, causing visual hallucinations 
  • Hallucinations occur even when eyes are closed

Safety Precautions and Contraindications

• Psilocybin is not for everyone 
  • Contraindicated for people with existing or predisposition to psychotic episodes or bipolar episodes
  • Having a first-​​degree relative with bipolar, schizophrenia, or schizotypal issues can be a rule-​​out condition
• Focus on adults (25 years or older) in clinical studies

Heroic Doses and Traditional Psychonauts

• “Heroic doses” are discussed in the informal community of psychonauts 
  • Difficult to translate this concept to scientific dataHeroic Dose of Psilocybin
• Refers to a 5‑gram dose of mushrooms, equivalent to 50 milligrams of psilocybin
• Concentration of psilocybin in different strains of mushrooms can vary greatly (0.5% to 2%) 
  • Sourcing and consistency are important for accurate dosing
  • Synthetic psilocybin provides more consistent dosing

Safety and Precautions

• People prone to psychotic episodes or with a family history of psychosis should not take psilocybin
• Individuals under 25 years old should avoid psilocybin
• People taking antidepressants that impact the serotonin system should not take psilocybin without consulting a physician

Music in Psilocybin Journeys

• Not just an incidental feature, but a major driver of the cognitive and emotional experience
• Can impact emotion, thought processes, and the overall journey
• Selection of music should be carefully considered for the duration of the journey (4 to 6 hours)

  Psilocybin Journey and Music

• Psilocybin journey lasts about 6 hours 
  • Begins 30–45 minutes after ingestion
  • Peak experience with intense emotions and anxiety
  • Gradual tapering off towards the 6‑hour mark
• Music played during clinical studies 
  • Matches and drives the contour of the psilocybin journey
  • Starts with low volume, classical music without vocals
  • Transitions to intense, high volume percussion music during peak experience
  • Softens to choral or melodic music, often with female voices
  • Ends with nature sounds and less synthetic elements

Cell Biology and Chemistry of Psilocybin Effects

• Psilocybin is converted to psilocin, which crosses the blood-​​brain barrier
• Psilocin predominantly activates the serotonin 2A receptor
• Serotonin 2A receptors are expressed on apical dendrites of pyramidal neurons 
  • These neurons communicate with other neurons in their environment
• Psilocybin increases lateral communication across brain areas 
  • Shift from a more modular, segmented brain to a more integrated, connected brain
• Reduction in hierarchical organization of the brain 
  • Sensory information flows more broadly through the thalamus
  • More blending of different senses, including interoception (sense of the body and its internal state)Psilocybin and Creativity
• Serotonin 2A receptor activation allows for broader, less precise, and less hierarchical activation of brain circuitry 
  • This can lead to blending of senses and experiences (e.g., sound linked to visual phenomena)
• Four prominent theories of brain networks activated during a psychedelic journey: 
  1. Changes in the Default Mode Network (responsible for spontaneous imagination and daydreaming)
  2. [Other three theories not mentioned]
  3. These theories are not competing; all have been shown to be true in different studies
  4. Controversy lies in which network changes the most to explain therapeutic outcomes

Functional Connectivity and Psilocybin

• Psilocybin expands the functional connectivity of the brain 
  • This expanded connectivity persists after the effects of psilocybin have worn off
• Study: “The Effects of Psilocybin and MDMA on Between-​​Network Resting State Functional Connectivity in Healthy Volunteers” 
  • Conducted by Robin Carhart-​​Harris at UCSF
  • Explored brain connectivity in healthy volunteers before and after taking psilocybin or MDMA
  • Found more extensive connectivity, pointing to enhanced lateral connectivity and less hierarchical organization
• Adaptive rewiring of the brain is the goal of effective psychedelic therapies 
  • Psilocybin does not seem to cause long-​​term issues with memory

Psilocybin and Creativity: Music Perception

• Study: “Increased Low-​​Frequency Brain Responses to Music after Psilocybin Therapy for Depression” 
  • Took advantage of music being played during therapeutic psilocybin sessions
  • Different types of music activate different brain areas (e.g., auditory cortex, ventral striatum, mesolimbic reward pathway)
  • Music can be broken down into high and low frequencies
  • Psilocybin may enhance the brain’s response to music, potentially increasing creativity and the experience of life outside of psychedelic journeysEffects of Psilocybin on Music Perception and Emotion
• Psilocybin changes one’s experience of music, not just during the journey, but also thereafter 
  • Increases positive emotions associated with music
  • Diminishes the sadness of music that tends to make one sad
• Study found that psilocybin rewires connections between emotion centers in the brain and networks controlling auditory perception of music 
  • Allows people to experience joy in response to music again
  • Reduces the capacity of sad music to make them feel sad and depressed

Key Experiences During a Psilocybin Journey

• Common phrases: letting go, ego dissolution, feelings of connectedness
• Scientific studies have explored subjective experiences that relate to positive therapeutic outcomes 
  • Enhanced feelings of connectedness
  • Dissolution of the ego, loss of one’s sense of self, and regaining of one’s sense of self
• Studies use rating scales to measure and compare experiences between different groups and studies

• Possibility of having a frightening or negative experience during a psilocybin journey
• Important to consider and understand the risks and potential negative outcomes associated with psilocybin use

  Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-​​Resistant Depression

• Study involved subjects undergoing two psilocybin sessions 
  • First session: 10mg of psilocybin (equivalent to 1g of psychedelic mushrooms)
  • Second session: 25mg of psilocybin (equivalent to 2.5g of psychedelic mushrooms)
• Subjects answered the Altered States of Consciousness Questionnaire 
  • Addressed the quality of experiences in the 25mg psilocybin session
• Key feature of a positive psychedelic experience: sense of oceanic boundlessness 
  • Feeling of massive connectedness with one’s environment, guides, oneself, past, present, people outside the room, the entire world, and maybe even the universe

Correlation between Experience and Therapeutic Outcomes

• Positive therapeutic outcomes (relief from major depression) correlated with: 
  • Strong experience of unity
  • Spiritual experience
  • Blissful state
  • Insightfulness
• Non-​​responders (no relief from depression) reported: 
  • Less experience of unity
  • Less spiritual experience
  • Less blissful state
  • Less insightfulness

Potential Real-​​Time Tools to Adjust Anxiety

• Dr. Matthew Johnson at Johns Hopkins is exploring the use of real-​​time respiration tools (breathing tools) to help adjust anxiety levels during psychedelic sessions 
  • Based on work in Dr. Andrew Huberman’s laboratoryDr. David Spiegel’s Laboratory and Physiological Psy
• Reduces anxiety quickly in real time
• Demonstrated in previous podcasts and a recent paper in Cell Reports Medicine
• Collaborative work with Dr. David Spiegel’s laboratory at Stanford School of Medicine
• One of the fastest and most effective ways to reduce autonomic arousal (anxiety or stress)
• Used in Dr. Matthew Johnson’s laboratory during psychedelic sessions to help participants self-​​direct their own calm

Therapeutic Use of Psilocybin: Practical Considerations for Dosing and Administration

• Paper goes through pharmacology of psilocybin, dosage, and administration
• Discusses contraindications, such as pregnancy, breastfeeding, and predisposition to psychosis
• Evidence for positive therapeutic outcomes: 
  • Strongest for cancer-​​related depression, cancer-​​related anxiety, and treatment-​​resistant depression
  • Moderate for alcohol use disorder, tobacco addiction
  • Least for obsessive-​​compulsive disorder, cluster headaches, migraines, and demoralization due to AIDS diagnosis

Psilocybin Dosages in Animal Studies

• Mouse studies often use high doses of psilocybin (1 mg/​​kg body weight) 
  • Equivalent to double or triple the human therapeutic dose
• Animal metabolism and difficulty in observing effects may contribute to higher doses

Therapeutic Use of Psilocybin

• Strongest evidence for treating major depression and intractable depression 
  • Clinical trials exploring psilocybin’s impact on mood disorders and addictive disorders
• Researchers pioneering legal, funding, and research efforts 
  • Robin Carhart-​​Harris, Matthew Johnson, Roland Griffiths, Nolan Williams, and others

Psilocybin Clinical Trials

• Around a dozen clinical trials exploring single or two-​​session psilocybin treatment (25–30mg range) 
  • Comparisons of psilocybin vs SSRIs or other antidepressants
  • Comparisons of psilocybin plus psychoanalysis or cognitive behavioral therapy vs therapy alone
• 60–75% of people with major depressive disorder report positive relief from depression with psilocybin 
  • Combined with proper therapeutic support, psilocybin produces large, rapid, and sustained antidepressant effects
  • Effect sizes 2.5 times greater than psychotherapy and 4 times greater than psychopharmacologic depression treatment studies
  • Combining drug therapy with talk therapy is more effective than either treatment alone

Understanding Psilocybin’s Effects

• Serotonin and activation of serotonin 2A receptor play a significant role in psilocybin’s effects 
  • Associated with the expansion of the neocortex across evolution
• Psilocybin journey can lead to enhanced ways of thinking, changed ways of thinking, and actual learning within the session
• Potential for psychedelics like psilocybin to provide relief for mental health issues that have been difficult to access
• Fundamental interest in understanding the brain, how it works, and how it can change through neuroplasticity

  Neuroplasticity and Psilocybin

• Neuroplasticity: the Holy Grail of the human nervous system 
  • Humans have long-​​lasting neuroplasticity throughout their lifespan
• Psilocybin: potential to achieve maximal plasticity in a short amount of time 
  • Must be used safely and with caution
  • Not recommended for those with predisposition to psychosis or bipolar disorder, or with a family history of these conditions
  • Not recommended for individuals 25 years of age or younger
  • Should only be used under the guidance of a dedicated and highly trained physician
• Psilocybin is an exciting and promising compound, but still in a preliminary stage 
  • Future episodes will revisit psilocybin and other psychedelics, including LSD, DMT, 5‑MeO-​​DMT, ketamine, MDMA, and mescaline